1 Department of Oral Pathology and Microbiology Peoplersquos Dental Academy MIG Block C Flat No 14 PCMS CampusPeoplersquos Hospital Bhopal Madhya Pradesh 462037 India
2Department of Oral Pathology and Microbiology Peoplersquos College of Dental Sciences and Research Center BhopalMadhya Pradesh 462037 India
3 Department of Oral Pathology and Microbiology Coorg Institute of Dental Sciences Virajpet Karnataka 571218 India4Department of Otolaryngology All India Institute of Medical Sciences (AIIMS) Raipur Chhattisgarh 492099 India5 Department of Oral Pathology and Microbiology Rishiraj Dental College Bhopal Madhya Pradesh 462036 India
Correspondence should be addressed to Megha Jain meghavipin12gmailcom
Received 24 September 2013 Accepted 8 December 2013
Academic Editor Mitsuhiro Ohshima
Copyright copy 2013 Megha Jain et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited
Apoptosis is a well definedmode of cell deathwhich plays an imperative role in the development regulation andmaintenance of thecell populations in multicellular organisms Apoptosis is implicated in both health and diseases Errors in apoptotic mechanismshave been allied to a wide range of pathologies including oral diseases This review presents an update focused on the role andsignificance of apoptosis in various oral diseases ranging from reactive to benign and malignant pathologies
1 Introduction
The word ldquoapoptosisrdquo is of Greek origin meaning ldquodroppingoffrdquo or ldquofalling offrdquo of petals fromflowers or leaves from treesThe term ldquoapoptosisrdquo was first introduced by Kerr et al It isan active inherently programmedphenomenonwhich can beinitiated or inhibited by a variety of environmental stimuliboth physiological and pathological Carl Vogt however firstdescribed the phenomenon more than 100 years earlier in1842 [1 2]
There are four major players which are involved intriggering and influencing the apoptotic process These arethe caspases Bcl-2 family of proteins tumor necrosis factorreceptor (TNF-R) superfamily and adaptor proteins [3]Caspases are a family of proteases and are classified intoinitiator caspases 2 8 9 and 10 effector caspases 3 6 and7 and inflammatory caspases 1 4 5 11 12 13 and 14 [3ndash5]Themembers of Bcl-2 family are a group of crucial regulatoryfactors in apoptosis which are characterized by presence ofconserved sequence motifs known as Bcl-2 homology (BH)domains They are categorised into proapoptotic proteins(Bad Bak Bax Bcl-rambo Bcl-xS Bid Bik Bim Blk BNIP3BokMtd Hrk and Nip3 inmammals and Egl-1 inC elegans)
and antiapoptotic proteins (A1Bfl1 Bcl-2 Bcl-w Bcl-xLBooDiva Mcl-1 NR-13 and Nrf3 in mammals BHRF-1E1B19K Ks-Bcl-2 LMW5-HL and ORF16 in bacteria andCed-9 in C elegans) [3 5]
Broadly based intrinsic and extrinsic classification is usedas platform to describe apoptotic signal cascade Extrin-sicdeath receptor activated pathway involves the initiationof apoptosis through ligation of plasma membrane deathreceptors whereas intrinsicmitochondrial cell death pathwayinvolves initiation of apoptosis as a result of disturbanceof intracellular homeostasis and mitochondria being criticalexecutioner of cell death While the initiation mechanisms ofthese pathway are different both pathways converge (com-mon pathway) resulting ultimately in cellular morphologicand biochemical alterations characteristic of apoptosis [5 6]Thus apoptosis is a tightly synchronised and efficient celldeath program requiring interplay of multitude of factors
Apoptosis is a genetically programmed form of cell deathwhich is indispensable for development and homeostasisof multicellular organism Although apoptotic cell deathplays an important role in maintenance of the normalphysiological state it may also be responsible for diseased
2 Journal of Oral Diseases
state of the body A dysfunctional apoptotic system canlead to either excessive removal or prolonged survival ofcells and thus dysregulated apoptosis is implicated in patho-genesis of a variety of diseases including oral patholo-gies The present review attempts to summarise and high-light the role and significance of apoptosis in various oraldiseases
2 Classification of Oral Diseases
(1) Reactive lesions
(i) Pyogenic granuloma(ii) Giant cell granuloma
(2) Inflammatory diseases
(i) Recurrent aphthous stomatitis (may fall intomore than one category)
311 Apoptosis and Pyogenic Granuloma Cells in multicel-lular organisms are inflicted with a variety of challengesto which they react by regeneration hyperplasia dysplasiahypertrophy atrophy or metaplasia depending on the natureof the challenge These modes of cellular adaptability involvemodulation of the balance between cell proliferation and celldeath [7] Pyogenic granuloma (PG) is one of the inflamma-tory hyperplasias seen in the oral cavity which may arise inresponse to various stimuli such as low-grade local irritationtraumatic injury or hormonal factors [8] Lower ISTR (in situ31015840-tailing reaction) labeling indices and more frequent Bcl-2Bax expression in PG than granulation tissue and capillaryhemangioma suggested that the low apoptotic rate in PG isclosely related to its characteristic rapid growth [9] It has alsobeen found that in pregnancy tumor female sex hormonesnot only enhance the expression of angiogenic factors but alsodecrease apoptosis of granuloma cells to extend angiogeniceffect [10] VEGF alone or in combination with Ang-2 couldprotect microvessels from apoptosis while Ang-2 alone hadno effectTherefore lack of VEGF is associated with apoptosisof endothelial cells and regression of granuloma [11]
312 Apoptosis and Giant Cell Granuloma Central giant celllesion (CGCL) and peripheral giant cell lesion (PGCL) ofthe jaws are characterized by multinucleated osteoclast-likegiant cells in a background of mononuclear cells [12 13]Pammer et al [13] demonstrated strong expression of Baxand Bak weak positivity for Bcl-2 and moderate positivityfor Bcl-x in majority of giant cells in PGCL and lesionscontaining osteoclast-like giant cells whereas only scatteredmononuclear cells were positive for Bax Bak and Bcl-2 Alsofrequency of apoptotic nuclei was 18 times higher in giantcells than in mononuclear cells suggesting that giant cellsof bone and soft tissue tumors are reactive cell forms andare not of neoplastic origin Both CGCL and PGCL showedincreased expression of Bax and Bcl-2 mRNA PGCL showeda higher apoptotic index (ratio BaxBcl-2) than CGCL alsoconfirmed by TUNEL analysis which might be associatedwith the different clinical behavior of CGCL and PGCL[12]
32 Apoptosis and Inflammatory Diseases
321 Apoptosis and Recurrent Aphthous Ulceration Recur-rent aphthous ulceration (RAU) is a common inflammatorycondition of the oral mucosa predominantly affecting liningoral mucosa [7] Recurrent aphthous like ulceration is acardinal feature of Behcetrsquos syndrome and is consistentlyassociated with it [14] Ultrastructurally normal oral mucosaof patients with RAU or Behcetrsquos syndrome revealed degen-erated apoptotic prickle cells and it was speculated that theonset of aphthous ulceration is closely related to phagocytosisof these apoptotic cells by intraepithelial mononuclear cells[15] RAU induces p53 immunoexpression which might berelated to its aetiopathogenesis [16]
Journal of Oral Diseases 3
322 Apoptosis and Diseases of Periodontium Periodontaldisease is an acute or chronic inflammatory condition whichdevelops as a result of imbalance in the equilibrium betweenthe host defence andmicrobial agents resulting in destructionof tooth-supporting tissue leading to mobility and tooth lossTUNEL positive cells positive staining with active caspase-3 Fas FasL p53 and chromatin condensation was found inthe inflammatory infiltrates of periodontitis patients whereasBcl-2 positivity was found in both periodontitis patients andhealthy controls thus concluding that apoptotic mechanismcould be implicated in the inflammatory process associatedwith periodontitis [17] A greater number of apoptotic ker-atinocytes than proliferative ones are found in periodon-titis patients only in the most apical part of the sulcuscompared to those with gingivitis [18] Monocytes are themost lysis-sensitive leukocytes for A actinomycetemcomitansleukotoxin which depends on caspase 1-activation [19] It isalso evidenced that live P gingivalis can induce significantapoptosis in primary human gingival epithelial cells between12 and 24 hours of challenge via gingipains dependentmechanism [20] Hydrogen sulfide can induce apoptosis ingingival epithelial cells and human gingival fibroblast inthe oral cavity which may cause a periodontal condition[21] Neutrophils when combined in a P gingivalis challengeassay of epithelial cells prevent epithelial cell apoptosis byphagocytosing P gingivalis and also protect the host fromthe harmful effects of its microbial proteases [22] It has alsobeen analysed that the increased fibroblast proliferation anda simultaneous decrease in apoptosis contribute to gingivalovergrowth [23]
33 Apoptosis and Immune-Mediated Diseases
331 Apoptosis and Oral Lichen Planus The hallmarkhistopathologic feature of lichen planus (LP) is the degen-eration of the basal layer of the epithelium Eosinophilicglobular bodies also known as colloid hyaline cytoid orCivatte bodies are also characteristic features of LP seen inthe basal layer and upper connective tissue and have beeninterpreted as degenerative keratinocytes Damage to thebasal layer appears to involve apoptosis as an early event [24]The following mechanisms are proposed for keratinocyteapoptosis
(1) T-cell-secreted TNF-120572 binding to TNF-120572 R1 receptoron keratinocyte surface
(2) T-cell surface CD95L (Fas ligand) binding to CD95(Fas) on the keratinocyte surface
(3) T-cell-secreted granzyme B entering the keratinocytevia perforin induced membrane pores
All these mechanisms activate caspase cascade resultingin keratinocyte apoptosis On the contrary reduced or absentapoptotic rate in inflammatory cells has been thought tocontribute to development of OLP [25]
One of the studies demonstrated that caspases 2 and 12were expressed in all samples and caspase-8 was expressed inmost of the samples of atrophic lichen planus suggesting theimportance of endoplasmic reticulum (ER) stress in inducing
apoptosis in OLPs However the activation of death receptorsin OLP cannot be ruled out [26] Increased apoptosis maycause a decrease in epithelial thickness reflected in the activityof the lesion It was found that apoptosis in the erosiveOLP was significantly more intense than in the reticulartype and both forms of OLP presented more apoptosis thanthe healthy oral mucosa [27] It has been demonstratedthat increased numbers of apoptosis were detected in OLPespecially in association with lymphocytic infiltration andhematoxylin-eosin staining being more sensitive in detectinghigher number of apoptotic nuclei than in situ end labeling[28] Expression of cell proliferation proteins like PCNAand apoptotic proteins like Bcl-2 and Bax was found to bealtered in OLP as seen in epithelial dysplasia suggestingtheir potential for malignant transformation [29] TUNELand caspase-3 expression showed absence or low rate ofapoptosis in inflammatory cells in OLP thus contributingto the persistence of the inflammation and favouring cancerdevelopment [30] Apoptosis in OLP seems to be correlatedwith granzyme B release while in oral cGVHD perforinseems to bemore important suggesting that subtle differencesseem to exist in their pathogenetic mechanisms [31]
332 Apoptosis and Erythema Multiforme Erythema multi-forme is a distinct dermatologic hypersensitivity pathologycharacterized by cutaneous or mucous lesions and eventuallyit can also involve both In their more severe forms theyappear with occasional visceral involvements It includeswide range of clinical patternsmdashEM minor EM majorStevens Johnson syndrome and toxic epidermal necrolysis[32] Cell death in EM is at least in part due to apoptosiswhich may be related to an altered expression of apoptosis-regulating proteins like p53 and Bcl-2 family proteins andactivation of FasFas-ligand system [33] ELISA and in vitroanalysis showed that sFasL secreted by PBMCs not ker-atinocytes plays a crucial role in the keratinocyte apoptosisand pathogenetic mechanism of TEN and SJS and serumsFasL level may be a good indicator for the early diagnosisof TEN and SJS [34] It has also been found that perforinmediates apoptosis in the pathogenesis of the epidermal cellchanges in SJS [35]
333 Apoptosis and Lupus Erythematosus Systemic lupuserythematosus (SLE) and discoid lupus erythematosus (DLE)are autoimmune diseases manifesting as erythematous orulcerative lesions with white striae radiating from the mar-gins [7] CD95 mutations are linked with loss of regulation ofB lymphocytes which predisposes to systemic autoimmunityincluding SLE [36] Autoantigens in SLE become clustered inand on the surface blebs of apoptotic cells and these cells playa central role in tolerizing B cells andT cells andmay drive theautoimmune response in systemic autoimmune disease [37]SLE is characterized by imbalance redox state which in turnis related to intracellular levels of glutathione and controlledproduction of reactive oxygen species and alteration in theintracellular redox environment of cells are critical for cellularimmune dysfunction activation of apoptotic enzymes andapoptosis [38] It has also been demonstrated that elevatedendothelial cell apoptosis strongly correlates with markedly
4 Journal of Oral Diseases
abnormal vascular function and elevated tissue factor levelsandmay represent an importantmechanism for developmentof atherothrombosis in SLE [39]
334 Apoptosis and Pemphigus Vulgaris Pemphigus is agroup of autoimmune blistering diseases characterized byloss of keratinocyte cell adhesion that leads to clinical blisterformation Induction of apoptosis or of proapoptotic proteinsby pemphigus IgGmay be (i) part of themechanism bywhichsera and IgG induce acantholysis or (ii) a consequence of lossof adhesion (anoikis) and a result of acantholysis [40] Fasligand levels are markedly increased in sera from untreatedpemphigus patients which is suggesting that FasFas lig-and cell death pathway plays amajor role in anoikis as seen inpemphigus [41] Hoechst 33342 staining andRT-PCR analysisshowed that apoptosis may be associated with acantholysisof pemphigus lesional epidermis and may play an importantrole in the pathogenesis of pemphigus [42] Apoptosis isobserved in the perilesional normal appearing tissue sug-gesting that it is an early phenomenon Also the process ofapoptosis may cause exacerbation or speeding of the bullaformation [43] But whether apoptosis is really essential foracantholysis in pemphigus is not clear Immunofluorescenceanalysis confirmed that PV IgG autoantibodies promoteapoptosis in HaCaT keratinocytes characterized by caspase-3activation Bcl-2 depletion and Bax expression [44]
335 Apoptosis and Epidermolysis Bullosa Epidermolysisbullosa is a hereditary vesiculobullous disease characterizedby blistering of the skin and oral mucosa due to basalkeratinocyte fragility [7] Experiment using cellular model ofEBS showed thatHaCaT cells were susceptible to apoptosis byactivation of caspases 3 and 8 but not caspase-9 or caspase-12 Moreover TNF-120572 release and the subsequent activationof the TNF-120572 receptor by an autocrineparacrine pathwaylink protein aggregates to cell death in this keratinocyteEBS cellular model Also susceptibility of keratinocytes tocaspase-8-mediated apoptosis is increased in mutated K14because of impairment of the cytoprotective mechanismmediated by K14-TRADD interaction [45]
336 Apoptosis and Oral Graft-versus-Host Diseases Graft-versus-host disease (GVHD) is characterized by an immune-mediated attack by donor immune cells against variousrecipient host cells and tissues Although donor and recip-ient are matched at major histocompatibility loci prior totransplantation GVHD occurs because differences exist atminor histocompatibility loci Programmed cell death orapoptosis has been evidenced as major constituent in thepathogenesis of GVHD Oral involvementmay be seen in 33ndash75 of patients who develop acute GVHD and in up to 80of patients affected by chronic GVHD making these lesionsuseful as a highly predictive index for the presence of systemicdisease The oral lesions of GVHD are clinically and histo-logically lichenoid in nature [46] CTL mediated apoptoticpathway predominates in GVHD Initiation can occur eitherwhen virus-specific cytotoxic T lymphocytes (CTL) bind totarget cells and release granzymes into the cells or when CTL
bind and activate the TNF family of receptors such as the Fas-receptor or TRAIL-receptor [46ndash48] Caspases and severalintracellular proteases participate in propagating and actuat-ing the apoptotic death signal through a proteolytic cleavagecascade [49 50] Phosphorylation pathways regulate signaltransduction cascades [51] However experimental murinemodels of acute GVHD demonstrated that apoptosis can beinduced even in the absence of immune cells suggestingexistence of an additional mechanism for target cell injury[52]
337 Apoptosis and Sjogrenrsquos Syndrome Sjogrenrsquos syndrome(SS) is an autoimmune disease characterized by diffuselymphoid cell infiltrates in the salivary and lacrimal glandsresulting in symptoms of dry mouth and eyes [53] Threeaspects of apoptosis are related to SS (i) defective apopto-sis could lead to lymphoid cell accumulation and chronicinflammation in exocrine glands (ii) increased apoptosis ofepithelial cells might explain the loss of secreting epitheliumand (iii) orderly destruction of cellular components mightinduce autoantibody production [54] Apoptosis of the acinarand ductal epithelial cells of the salivary and lacrimal glandsmay be induced by either CTL through the release perforinand granzyme B or the interaction of Fas ligand expressedby T lymphocytes with Fas on epithelial cells [55] On thecontrary others believed that Fas-induced apoptosis amongSS salivary glands is a rare event despite their abundantexpression since infiltratingmononuclear cells seem to escapeapoptosis resulting in foci of inflammatory cells [56] 120 kDa120572-Fodrin is an important autoantigen in the developmentof SS in animal models and SS patients Anti-Fas antibody-induced apoptosis and an increase in the activities of calpainand caspases may be involved in the progression of 120572-fodrin proteolysis and tissue destruction in the developmentof SS [53] In vitro analysis demonstrated that apoptosistriggered by anti-Ro and anti-La could be responsible for theimpairment of the secretory function in the salivary glands[57]
34 Apoptosis and Virus Associated Diseases Various typesof viruses have been involved in the pathogenesis of dif-ferent oral lesions the commonest being herpes simplexvirus (HSV) human papillomaviruses (HPV) and humanimmunodeficiency virus (HIV) Virus infected cells can oftenbe recognized and destroyed by apoptotic processes initiatedby either CTL or certain cytokines Many viruses directlyinduce apoptosis during infection which is at least partiallyresponsible for the various viral pathologies Many viruseshave evolved with multiple distinct mechanisms to blockthe premature apoptosis of infected cells either facilitatingthe maintenance of persistent infection or prolonging thesurvival of lytically infected cells such that the production ofprogeny virus is maximized [58] Examples include blockageof apoptosis by viral BCL-2 (vBCL-2) homologues [59] uti-lization of the phosphatidylinositol 3-kinase-Akt signallingpathway [60] or suppression of inducers of apoptosis suchas p53 [61]
HSV infection triggers apoptosis in infected cells How-ever proteins synthesized later in infected cells prevent
Journal of Oral Diseases 5
apoptotic cell death from ensuingThis apoptoticmodulationhas a role in the development of herpetic disease [62] HSV-1-induced apoptosis of immature dendritic cells is associatedwith downregulation of the cellular FLICE-inhibitory protein(c-FLIP) in a proteasome-independent manner [63] HSV-1triggers apoptosis in CNS neurons and causes encephalitis inadult subjects [64] HSV-1 enhances apoptosis via expressionof both Fas and Fas ligand on the surface of neonatalneutrophils [65]
High risk HPV oncoproteins E6 E7 and E5 can mod-ulate host mediated apoptosis by inhibiting death receptorsignaling and thus regulate the survival of infected cells [66]HPV E6 proteins inhibit apoptosis in both p53-dependentand p53-independent manners HPV-18 E6 inhibits Bak-induced apoptosis in differentiating keratinocytes in whichHPV replicates It was also suggested that Bak is probably thefirst naturally occurring target of ubiquitin ligase E6AP [67]
HIV infection usually leads to progressive immunod-eficiency and loss of immune competence associated withdeclines in both the functionality and the number of CD4+lymphocytes which in turn is related to various viral andimmunological processes Proposed virus-mediated mech-anisms include toxicity caused by accumulation of uninte-grated viral DNA alteration in membrane permeability dueto budding of viral particles and terminal differentiationAmong the immunological mechanisms are killing by spe-cific CTL and signaling through the CD4 molecule leadingto CD4+ lymphocytes apoptosis [68] Apoptosis in HIV maybe stimulated by environmental stress toxins and removalof growth factors and may be mediated by one of thesedeath inducing ligands TNF FasL and TRAIL [69] Manyof the proteins that are encoded by the HIV genome havebeen found to have pro- andor antiapoptotic qualities HIVsurface glycoprotein gp120 cross-links CD4 and primes cellsfor apoptosis HIV-1 can also induce apoptosis ldquofrom withinrdquovia expression of certain viral genes such as tat nef vpu andvpr [68 69]
35 Apoptosis and Benign Entities
351 Apoptosis and Benign Odontogenic Cysts and Tumors
(1) Apoptosis and RadicularApical Cyst Radicular cysts arethe most common cystic lesions of the jaws and representa periapical inflammatory disease evoked by infected andnecrotic dental pulp Apoptosis was found to be alwayspresent in the epithelium of the apical radicular cyst Higherapoptotic index (AI) and bcl-2 index (bcl-2I) were found inlesions with atrophic compared to hyperplastic epitheliumbut the difference was statistically insignificant However apositive and significant correlation was found between AIand bcl-2I [70] Epithelium of radicular and residual cystsshowed expression of apoptosis related factors like ssDNAp53 Bax Bcl-2 caspase-3 Fas Fas-L and Ki-67 antigensuggesting their role in the pathophysiologic activity ofperiapical inflammatory lesions Such factors may be affectedby the structure of lining epithelium and the degree ofinflammatory change since Ki-67 and ssDNA reactivity inRCs with intense inflammatory reactions or with thick lining
epithelium were significantly stronger than those RCs withless inflammation or with thin lining [71] Caspase-3 andKi-67 expression was significant in hyperplastic epitheliumrelated to intense inflammation whereas Bcl-2 expressionwas significantly higher in atrophic epithelium of DCs thanRCs suggesting that although they may have different patho-genetic mechanism they have similar biological behavior inthe presence of intense inflammatory infiltrate [72]
(2) Apoptosis and Dentigerous Cyst The epithelial lining ofDCs has shown TUNEL Ki-67 and p53 positivity but theexpression was weak as compared to OKCs indicating thatapoptosis is involved in cyst formation and maintainingthe regular thickness of the lining epithelium in DCs [73]Bcl-2 positivity was significantly higher in atrophic epithe-lium of DCs than that of RCs suggesting that presence ofinflammation inhibits the Bcl-2 expression and both cystshave similar biological behavior in the presence of intenseinflammatory infiltrate [72] whereas other demonstrated thatBcl-2 expression was almost completely negative in DCs andRCs compared to OKCs [74]
(3) Apoptosis and Odontogenic KeratocystKeratocystic Odon-togenic Tumor Keratocystic odontogenic tumor (KCOT)also known as odontogenic keratocyst (OKC) was recentlyclassified as a benign neoplasia due to the aggressive clinicalbehavior The proliferation index and apoptotic index werefound to be higher and with distinct pattern in both sporadicand nevoid basal cell carcinoma syndrome (NBCCS) KCOTscompared to DCs reflecting its high cell turnover andreinforcing its classification as an odontogenic tumor [75]Lack of p16 expression in KCOT compared to strong ormoderate p16 expression in RCs and follicular cysts couldbe related to the increased aggressive behavior invasivenessand high frequency of recurrences found in KCOT [76]Overexpression of cyclin Dl and p53 in syndromic OKCscould be considered as hallmark of a mutated cellular phe-notype and more aggressive clinical behaviour compared tosporadic KCOTs which were negative for these oncoproteins[77] Strong Bcl-2 overexpression in OKCs suggests its rolein extension of cell survival leading to the peculiar aggressivegrowth pattern and can be useful to differentiate OKC fromother odontogenic cysts [74] TUNEL positive cells wereobserved in the surface layers of OKCs whereas no positivitywas seen in the basal or intermediate layers of OKCs andDCs Also Ki67-positive ratio and p53-positive ratio in theintermediate layer were the highest in OKCs and Bcl-2-positive cells were discernible exclusively in the basal layerof OKCs signifying that subsequently OKCs are seen ascystic lesions but not as tumor masses [73] There is nosignificant difference in proliferative activity and apoptosisin OKCs associated with or without impacted teeth orbetween the unilocular ormultilocular variants [78] Survivinimmunoexpression was positive in all cases of OKCs while allperiapical cysts were negative suggesting its contribution toviolent behavior of OKCs [79]
(4) Apoptosis and Ameloblastomas Ameloblastoma isthe most frequently encountered tumor arising from
6 Journal of Oral Diseases
odontogenic epithelium and is characterized by a benign butlocally invasive behavior with a high risk of recurrence [80]
RT-PCR and IHC showed expression of cytochrome cAPAF-1 caspase-9 and AIF in tooth germs and benign andmalignant ameloblastomas suggesting that themitochondria-mediated apoptotic pathway has a role in apoptotic celldeath of normal and neoplastic odontogenic epithelium andmight be involved in oncogenesis cytodifferentiation andmalignant transformation of odontogenic epithelium [81]
Granular cells basal cells desmoplastic ameloblastomasand ameloblastic carcinomas showed immunoreactivity forthe BH3-only proteins (Bid Bim Bad Noxa and Puma)whereas keratinising cells of acanthomatous ameloblastomasshowed no reactivity suggesting that these proteins mightbe involved in tumor cell differentiation of ameloblastomas[82] TNF-120572 TRAIL and their receptors were also found tobe expressed in tooth germs and ameloblastomas provingtheir role in cytodifferentiation of odontogenic epitheliumand tissue structuring of ameloblastomas [83] Similarlyexpression of Fas FasL caspase-3 and ssDNA has also beendemonstrated in various patterns in tooth germs and benignand malignant ameloblastomas [84]
352 Apoptosis and Benign Epithelial Tumor
(1) Apoptosis and Squamous PapillomaOral squamous papil-loma (OSP) is a frequent benign tumorous lesion associatedwith HPV OSP consists of proliferation of the stratifiedsquamous epithelium resulting in a papillary or verrucousexophytic mass and has got site predilection for the tongueand soft palate but any surface of the oral cavity can beaffected [85 86] Carneiro et al performed immunohisto-chemical assay on 12 OSP cases utilizing BP53-12 and Pab240antibodies for p53 protein and found that immunostainingfor protein p53 was primarily negative or weakly positivein all cases (in all epithelial layers) except one case whichindicates the benign nature of the lesions evidenced by theirslow development and less chances of becoming malignantIntense staining in one slide for both immunomarkers in allthe epithelial layers could be attributed to the presence ofvirus with high oncogenic potential (HPV 16 and 18) or tothe presence of coexisting external factors [85]
36 Apoptosis and Premalignant and Malignant Entities
361 Apoptosis and Actinic Cheilitis Actinic cheilitis (AC) isa common condition caused by damage to the lips throughexposure to sunlight and has the potential to undergomalignant transformation into squamous cell carcinoma [87]Overexpression of p53 was found in AC as compared tonormal lip and oral mucosa Bcl-2 expression was higherin AC than in oral mucosa but it was significantly reducedas compared with normal lip Thus it was suggested thatDNA-damaged cells by UV radiation in AC are eliminatedby apoptosis Also both p53 and bcl-2 play an important rolein regulating malignant transformation in AC [88]
362 Apoptosis and Oral Leukoplakia It has been sug-gested that a change in apoptosis accompanies the onset
of invasion in a premalignant lesion of the human oralcavity and oropharynx AI increased progressively fromnormal to carcinoma in situ (CIS) but fell in SCC withmaximum apoptotic index (AI) mitotic index (MI) ratioin CIS The position of apoptotic bodies was localised tothe deepest layers in normal and dysplastic epithelia butbecame generalised in CIS and SCC [89] Greater expressionof oncoproteins MDM2 and Bcl-2 was seen in leukoplakiawith altered keratinocyte maturation than OLP case whereasexpression of wt-p53 and p21 was higher in OLP compared toleukoplakia cases In spite of divergent outcome of apoptoticsignalling proteins no significant difference in the number ofapoptotic epithelial cells was observed between leukoplakiaand OLP cases [90] Increased mitotic apoptotic and Ki-67 index indicate unfavourable prognosis of leukoplakia [91]Abundance of p27 expression in oral leukoplakia may beassociated with inhibition of cell proliferation leading toapoptosis of premalignant tumor cells thus preventing tumorprogression [92] It is hypothesised that the antiapoptoticability of Epstein-Barr virus (EBV) may result in alteredexpression of apoptosis-associated proteins in oral hairyleukoplakia Except p53 which appears to be overexpressedthere is only slight alteration in immunoexpression of otherapoptosis-associated proteins in OHL [93]
363 Apoptosis and Oral Squamous Cell Carcinoma Theaccumulation of neoplastic cells can occur through enhancedproliferation diminished cell turnover or a combination ofboth processes Tumor cells from a wide variety of humancancers have been shown to exhibit increased survival andresistance to apoptosis [94] There are two major ways thatcould downregulate cancer cell apoptosis (1) somatic andnonsomatic mutation and loss of expression of proapoptoticmolecules and (2) overexpression of apoptosis inhibitorymolecules Mutations within caspase family proteases are notuncommon in malignancies [95] Caspase-7 proved to bean independent prognosticator and predictor of locoregionalrecurrence in patients of OSCC [96] Several alterations thatinhibit both the death receptor and mitochondrial pathwaysvia caspases have also been identified including overexpres-sion of IAPs activation of PI3k or Akt and posttranslationalmodifications of caspases [94]
In pathological settings Bcl-2 gene family appears toact synergistically with oncogenes and tumor suppressorgenes [97] Positive Bcl-2 expression is associated with highertumor grading higher tumor mitotic index higher index ofatypical mitoses and microfocal pattern of tumor invasivemargins [98] In OSCC compared with oral epitheliumthere is a decreased Bcl-2 expression a lowered Bcl-2Baxratio and increased apoptosis Expression of Bax correlatedwith histological tumor grading in OSCC [99] whereasothers found that expression of Bak may be useful for bettercharacterizing and predicting the prognosis of OSCC [100]
Aberrations of the p53 gene and overexpression of its pro-tein are widely recognized markers of malignancy includingOSCC It was found that there is a negative correlation of p53immunoexpression with histologic grade of differentiationIn patients without neck node metastases p53 showed astrong correlation with survival [101] On the contrary
Journal of Oral Diseases 7
another study showed that expression of p53 protein did notbehave as amarker of prognostic value in patients withOSCC[102]
As cancer is characterized by uncontrolled cell prolif-eration markers of proliferation such as Ki67 and PCNAhave been studied extensively in neoplastic lesions Expres-sion of both p53 and Ki67 correlated significantly with thehistopathological stage of the tumor However expression ofp53 was not correlated with that of Ki67 [103]
HPV infection andor p53 mutations are implicated incarcinogenesis of oral SCC but are not mutually exclusiveevents Moreover decrease in apoptosis is more closelyrelated to p53 mutation than HPV infection [104]
Survivin has got a versatile role in modulating celldivision and apoptosis in cancer Low survivin expressioncorrelated statistically significantly with better survival ratesbut not with age sex tumor size the presence of lymphnode or distant metastases [105] Survivin was found tobe preferentially expressed in nonadvanced nonmetastaticand chemotherapy-sensitive OSCC [106] On the contraryincreased expression of survivin was found in high-gradetumors suggesting its contribution to apoptosis resistancein response to therapy [107] Also significant correlationbetween survivin expression lymph node metastasis andproliferation was revealed but not with differentiationmicrovessel density or TNM staging [108]
Upregulation of FasL and downregulation of Fas havebeen shown to occur in oral carcinogenesis possibly con-tributing to both cancer cell survival and evasion of the hostimmune assault through induction of apoptosis in T cellsthat would normally kill tumor cells [109] Moreover it hasbeen found that Fas is expressed in low quantities in OSCCwhereas FasL expression correlates negatively with degree ofdifferentiation and apoptosis in OSCC [110] Thus variousproteins (apoptotic and antiapoptotic) have got a significantbearing in initiation progression and prognosis of OSCC
37 Apoptosis and Salivary Gland Tumors Salivary glandtumors (SGT) are relatively uncommon neoplasms withwidely variable histopathologic and biologic characteristicsP53bcl-2 immunostaining reactivity could be helpful indemonstrating SGT behavior in terms of progression andextent of invasion since all malignant salivary gland tumorswere positive whereas 70 of pleomorphic adenomas (PA)showed negative expression [111] Similarly Nordkvist et alfound p53 overexpression in 20 of the malignant SGT withthe highest prevalence in PLGA squamous cell carcinomaand CaXPA and the lowest in adenoid cystic carcinomaand acinic cell carcinoma but none of the benign PA [112]Expression of p53 in malignant tumors bore no correlationto local recurrence metastatic disease or survival of thepatients [113] Bcl-2 protein expression was found virtuallyin all benign and malignant SGT suggesting its role in thedevelopment and proliferation of these tumors via inhibitionof apoptosis [114] p53 expression apoptotic index and bcl-2 protein are potential prognostic parameters in salivarygland adenoid cystic carcinoma [115] Frequency of apoptosisis inversely related to bcl-2 but not to Bax expression inSGT [116] Survival probability of patients who demonstrated
positive staining for c-erbB-2 or TUNEL or both was lowerthan those with negative staining [117]
4 Conclusion
Understanding the mechanistic machinery of apoptosis iscrucial because it influences both health and disease beinginitiated by various physiologic and pathologic stimuliMore-over the extensive involvement of apoptosis in the patho-genesis of various oral diseases and meticulous knowledgeabout it prompt it to therapeutic intervention at differentcheckpoints This review is an attempt to provide an updateon the crucial role and importance of apoptosis in various oralpathologies
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] A Lawen ldquoApoptosis an introductionrdquo BioEssays vol 25 no 9pp 888ndash896 2003
[2] J F Kerr A H Wyllie and A R Currie ldquoApoptosis abasic biological phenomenon with wide-ranging implicationsin tissue kineticsrdquo British Journal of Cancer vol 26 no 4 pp239ndash257 1972
[3] A Strasser L OrsquoConnor and V M Dixit ldquoApoptosis signalingrdquoAnnual Review of Biochemistry vol 69 pp 217ndash245 2000
[4] N Singh ldquoApoptosis in health and disease and modulation ofapoptosis for therapy an overviewrdquo Indian Journal of ClinicalBiochemistry vol 22 no 2 pp 6ndash16 2007
[5] T-J Fan L-H Han R-S Cong and J Liang ldquoCaspase familyproteases and apoptosisrdquo Acta Biochimica et Biophysica Sinicavol 37 no 11 pp 719ndash727 2005
[6] P C Ashe and M D Berry ldquoApoptotic signaling cascadesrdquoProgress in Neuro-Psychopharmacology and Biological Psychia-try vol 27 no 2 pp 199ndash214 2003
[7] L L Loro O K Vintermyr and A C Johannessen ldquoApoptosisin normal and diseased oral tissuesrdquoOral Diseases vol 11 no 5pp 274ndash287 2005
[8] H Jafarzadeh M Sanatkhani and N Mohtasham ldquoOral pyo-genic granuloma a reviewrdquo Journal of Oral Science vol 48 no4 pp 167ndash175 2006
[9] T Nakamura ldquoApoptosis and expression of BaxBcl-2 proteinsin pyogenic granuloma a comparative study with granulationtissue and capillary hemangiomardquo Journal of Cutaneous Pathol-ogy vol 27 no 8 pp 400ndash405 2000
[10] K Yuan L-Y C Wing and M T Lin ldquoPathogenetic roles ofangiogenic factors in pyogenic granulomas in pregnancy aremodulated by female sex hormonesrdquo Journal of Periodontologyvol 73 no 7 pp 701ndash708 2002
[11] K Yuan and M T Lin ldquoThe roles of vascular endothelialgrowth factor and angiopoietin-2 in the regression of pregnancypyogenic granulomardquo Oral Diseases vol 10 no 3 pp 179ndash1852004
[12] F R Amaral V F Bernardes A P Duarte et al ldquoQuantitativeexpression analysis of apoptoticantiapoptotic genes and associ-ationwith immunolocalization of BAX andBCL-2 in peripheral
8 Journal of Oral Diseases
and central giant cell lesions of the jawsrdquo Tumor Biology vol 32no 5 pp 997ndash1003 2011
[13] J Pammer W Weninger H Hulla P Mazal and R HorvatldquoExpression of regulatory apoptotic proteins in peripheral giantcell granulomas and lesions containing osteoclast-like giantcellsrdquo Journal of Oral Pathology and Medicine vol 27 no 6 pp267ndash271 1998
[14] C Scully and S Porter ldquoOral mucosal disease recurrentaphthous stomatitisrdquo British Journal of Oral and MaxillofacialSurgery vol 46 no 3 pp 198ndash206 2008
[15] T Honma T Saito and Y Fujioka ldquoPossible role of apoptoticcells of the oral epithelium in the pathogenesis of aphthousulcerationrdquoOral Surgery Oral Medicine and Oral Pathology vol59 no 4 pp 379ndash387 1985
[16] J F N Pinto Rodrigues C T Fujiyama Oshima A P RibeiroPaiotti M Franco S S Miki Ihara and D A RibeiroldquoExpression of apoptosis regulatory proteins p53 bcl-2 andbax in recurrent aphthous ulcerationrdquo Journal of the EuropeanAcademy of Dermatology and Venereology vol 26 no 10 pp1247ndash1251 2012
[17] J Gamonal A Bascones A Acevedo E Blanco and A SilvaldquoApoptosis in chronic adult periodontitis analyzed by in situDNA breaks electron microscopy and immunohistochem-istryrdquo Journal of Periodontology vol 72 no 4 pp 517ndash525 2001
[18] F Jarnbring E Somogyi J Dalton A Gustafsson and BKlinge ldquoQuantitative assessment of apoptotic and prolifera-tive gingival keratinocytes in oral and sulcular epithelium inpatients with gingivitis and periodontitisrdquo Journal of ClinicalPeriodontology vol 29 no 12 pp 1065ndash1071 2002
[19] P Kelk A Johansson R Claesson L Hanstrom and S KalfasldquoCaspase 1 involvement in human monocyte lysis induced byActinobacillus actinomycetemcomitans leukotoxinrdquo Infectionand Immunity vol 71 no 8 pp 4448ndash4455 2003
[20] P G Stathopoulou J C Galicia M R Benakanakere C AGarcia J Potempa and D F Kinane ldquoPorphyromonas gingi-valis induce apoptosis in human gingival epithelial cells througha gingipain-dependent mechanismrdquo BMC Microbiology vol 9article 107 2009
[21] T Murata K YaegakiW Qian et al ldquoHydrogen sulfide inducesapoptosis in epithelial cells derived from human gingivalrdquoJournal of Breath Research vol 2 no 1 Article ID 017007 2008
[22] J C Galicia M R Benakanakere P G Stathopoulou and DF Kinane ldquoNeutrophils rescue gingival epithelial cells frombacterial-induced apoptosisrdquo Journal of Leukocyte Biology vol86 no 1 pp 181ndash186 2009
[23] A Kantarci P Augustin E Firatli et al ldquoApoptosis in gingivalovergrowth tissuesrdquo Journal of Dental Research vol 86 no 9pp 888ndash892 2007
[24] VAMurrah andE PGilchrist ldquoAssessment of apoptosis in orallichen planusrdquoOral Surgery OralMedicine Oral Pathology OralRadiology and Endodontics vol 82 no 2 pp 209ndash210 1996
[25] M R Roopashree R V Gondhalekar M C Shashikanth JGeorge S H Thippeswamy and A Shukla ldquoPathogenesis oforal lichen planus a reviewrdquo Journal of Oral Pathology andMedicine vol 39 no 10 pp 729ndash734 2010
[26] R Mattila and S Syrjanen ldquoCaspase cascade pathways inapoptosis of oral lichen planusrdquo Oral Surgery Oral MedicineOral Pathology Oral Radiology and Endodontology vol 110 no5 pp 618ndash623 2010
[27] J M C Brant A C Vasconcelos and L V Rodrigues ldquoRole ofapoptosis in erosive and reticular oral lichen planus exhibiting
[28] B K Bloor F K Malik E W Odell and P R MorganldquoQuantitative assessment of apoptosis in oral lichen planusrdquoOral Surgery OralMedicine Oral Pathology Oral Radiology andEndodontics vol 88 no 2 pp 187ndash195 1999
[29] F A C G D Sousa T C Paradella Y R Carvalho and L EB Rosa ldquoImmunohistochemical expression of PCNA p53 baxand bcl-2 in oral lichen planus and epithelial dysplasiardquo Journalof oral science vol 51 no 1 pp 117ndash121 2009
[30] C Bascones-Ilundain M A Gonzalez-Moles G Esparza-Gomez J A Gil-Montoya and A Bascones-Martınez ldquoImpor-tance of apoptoticmechanisms in inflammatory infiltrate of orallichen planus lesionsrdquo Anticancer Research vol 26 no 1 pp357ndash362 2006
[31] V N Pimentel L S de Matos T C B Soares et al ldquoPerforinand granzyme B involvement in oral lesions of lichen planusand chronic GVHDrdquo Journal of Oral Pathology and Medicinevol 39 no 10 pp 741ndash746 2010
[32] L R Oliveira and S Zucoloto ldquoErythema multiforme minor arevisionrdquoTheAmerican Journal of Infectious Diseases vol 4 no4 pp 224ndash231 2008
[33] E Chrysomali F Lozada-Nur N P Dekker S I Papanicolaouand J A Regezi ldquoApoptosis in oral erythema multiformerdquo OralSurgery Oral Medicine Oral Pathology Oral Radiology andEndodontics vol 83 no 2 pp 272ndash280 1997
[34] R Abe T Shimizu A Shibaki H Nakamura HWatanabe andH Shimizu ldquoToxic epidermal necrolysis and Stevens-Johnsonsyndrome are induced by soluble fas ligandrdquo The AmericanJournal of Pathology vol 162 no 5 pp 1515ndash1520 2003
[35] S Inachi H Mizutani and M Shimizu ldquoEpidermal apop-totic cell death in erythema multiforme and Stevens-Johnsonsyndrome contribution of perforin-positive cell infiltrationrdquoArchives of Dermatology vol 133 no 7 pp 845ndash849 1997
[36] A K Vaishnaw E Toubi S Ohsako et al ldquoThe spectrumof apoptotic defects and clinical manifestations includingsystemic lupus erythematosus in humans with Cd95 (FasApo-1)mutationsrdquoArthritis and Rheumatism vol 42 no 9 pp 1833ndash1842 1999
[37] S White and A Rosen ldquoApoptosis in systemic lupus erythe-matosusrdquo Current Opinion in Rheumatology vol 15 no 5 pp557ndash562 2003
[38] D Shah S Sah and S K Nath ldquoInteraction between glu-tathione and apoptosis in systemic lupus erythematosusrdquoAutoimmunity Reviews vol 12 no 7 pp 741ndash751 2013
[39] S Rajagopalan E C Somers R D Brook et al ldquoEndothelial cellapoptosis in systemic lupus erythematosus a common pathwayfor abnormal vascular function and thrombosis propensityrdquoBlood vol 103 no 10 pp 3677ndash3683 2004
[40] M Bektas P Jolly and D S Rubenstein ldquoApoptotic pathwaysin pemphigusrdquo Dermatology Research and Practice vol 2010Article ID 456841 2010
[41] M Puviani A Marconi E Cozzani and C Pincelli ldquoFas ligandin pemphigus sera induces keratinocyte apoptosis through theactivation of caspase-8rdquo Journal of Investigative Dermatologyvol 120 no 1 pp 164ndash167 2003
[42] B H Roh K U Whang M K Cho Y L Park J S Lee andCW Lee ldquoA study of apoptosis in pemphigus vulgarisrdquo KoreanJournal of Dermatology vol 45 no 7 pp 650ndash658 2007
[43] P Deyhimi and P Tavakoli ldquoStudy of apoptosis in oral pem-phigus vulgaris using immunohistochemical marker Bax and
Journal of Oral Diseases 9
TUNEL techniquerdquo Journal of Oral Pathology andMedicine vol42 no 5 pp 409ndash414 2013
[44] B Pelacho C Natal A Espana I Sanchez-Carpintero MJ Iraburu and M J Lopez-Zabalza ldquoPemphigus vulgarisautoantibodies induce apoptosis inHaCaT keratinocytesrdquo FEBSLetters vol 566 no 1ndash3 pp 6ndash10 2004
[45] K Yoneda T Furukawa Y-J Zheng et al ldquoAn autocrineparacrine loop linking keratin 14 aggregates to tumor necrosisdactor 120572-mediated cytotoxicity in a keratinocyte model ofepidermolysis bullosa simplexrdquo Journal of Biological Chemistryvol 279 no 8 pp 7296ndash7303 2004
[46] P P Sedghizadeh C M Allen K E Anderson D H Kim JR Kalmar and J C Lang ldquoOral graft-versus-host disease andprogrammed cell death pathogenetic and clinical correlatesrdquoOral Surgery OralMedicine Oral Pathology Oral Radiology andEndodontics vol 97 no 4 pp 491ndash498 2004
[47] T A Graubert J H Russell and T J Ley ldquoThe role of granzymeB in murine models of acute graft-versus-host disease and graftrejectionrdquo Blood vol 87 no 4 pp 1232ndash1237 1996
[48] N Zavazava and D Kabelitz ldquoAlloreactivity and apoptosisin graft rejection and transplantation tolerancerdquo Journal ofLeukocyte Biology vol 68 no 2 pp 167ndash174 2000
[49] A Sarin E KHaddad and PAHenkart ldquoCaspase dependenceof target cell damage induced by cytotoxic lymphocytesrdquo Jour-nal of Immunology vol 161 no 6 pp 2810ndash2816 1998
[50] M Enari H Hug and S Nagata ldquoInvolvement of an ICE-likeprotease in Fas-mediated apoptosisrdquo Nature vol 375 no 6526pp 78ndash81 1995
[51] T H Holmstrom and J E Eriksson ldquoPhophorylation basedsignaling in Fas receptor mediated apoptosisrdquo Critical Reviewsin Immunology vol 20 pp 121ndash152 2000
[52] Y H Yoo A C Gilliam D Whitaker-Menezes R Korngoldand G F Murphy ldquoExperimental induction and ultrastructuralcharacterization of apoptosis in marine acute cutaneous graft-versus-host diseaserdquo Archives of Dermatological Research vol289 no 7 pp 389ndash398 1997
[53] Y Hayashi K Yayagi and N Haneji ldquoInvolvement of apoptoticprotease cascade for tissue destruction in Sjogrenrsquos syndromerdquoArchivum Immunologiae et Therapiae Experimentalis vol 48no 5 pp 399ndash403 2000
[54] A I Bolstad and R Jonsson ldquoThe role of apoptosis in Sjogrenrsquossyndromerdquo Annals of Internal Medicine vol 149 no 1 pp 25ndash29 1998
[55] P Manganelli and P Fietta ldquoApoptosis and Sjogren syndromerdquoSeminars in Arthritis and Rheumatism vol 33 no 1 pp 49ndash652003
[56] M Ohlsson K Skarstein A I Bolstad A C Johannessen andR Jonsson ldquoFas-induced apoptosis is a rare event in Sjogrenrsquossyndromerdquo Laboratory Investigation vol 81 no 1 pp 95ndash1052001
[57] M Sisto S Lisi D Lofrumento M DrsquoAmore P Scagliusiand VMitolo ldquoAutoantibodies from Sjogrenrsquos syndrome triggerapoptosis in salivary gland cell linerdquo Annals of the New YorkAcademy of Sciences vol 1108 pp 418ndash425 2007
[58] L S Young C W Dawson and A G Eliopoulos ldquoViruses andapoptosisrdquo British Medical Bulletin vol 53 no 3 pp 509ndash5211997
[59] B M Polster J Pevsner and J M Hardwick ldquoViral Bcl-2homologs and their role in virus replication and associateddiseasesrdquo Biochimica et Biophysica Acta vol 1644 no 2-3 pp211ndash227 2004
[60] S Cooray ldquoThe pivotal role of phosphatidylinositol 3-kinase-Akt signal transduction in virus survivalrdquo Journal of GeneralVirology vol 85 no 5 pp 1065ndash1076 2004
[61] J G Teodoro andP E Branton ldquoRegulation of apoptosis by viralgene productsrdquo Journal of Virology vol 71 no 3 pp 1739ndash17461997
[62] M L Nguyen and J A Blaho ldquoApoptosis during herpes simplexvirus infectionrdquo Advances in Virus Research vol 69 pp 67ndash972006
[63] A Kather M J Raftery G Devi-Rao et al ldquoHerpes simplexvirus type 1 (HSV-1)-induced apoptosis in human dendriticcells as a result of downregulation of cellular FLICE-inhibitoryprotein and reduced expression of HSV-1 antiapoptotic latency-associated transcript sequencesrdquo Journal of Virology vol 84 no2 pp 1034ndash1046 2010
[64] L Aurelian ldquoHSV-induced apoptosis in herpes encephalitisrdquoCurrent Topics in Microbiology and Immunology vol 289 pp79ndash111 2005
[65] J Ennaciri J Menezes F Proulx and B J Toledano ldquoInductionof apoptosis by herpes simplex virus-1 in neonatal but not adultneutrophilsrdquo Pediatric Research vol 59 no 1 pp 7ndash12 2006
[66] A M Fuentes-Gonzalez A Contreras-Paredes J Manzo-Merino and M Lizano ldquoThe modulation of apoptosis byoncogenic virusesrdquo Virology Journal vol 10 article 182 2013
[67] MThomas and L Banks ldquoInhibition of Bak-induced apoptosisby HPV-18 E6rdquo Oncogene vol 17 no 23 pp 2943ndash2954 1998
[68] M Roshal Y Zhu and V Planelles ldquoApoptosis in AIDSrdquoApoptosis vol 6 no 1-2 pp 103ndash116 2001
[69] N W Cummins and A D Badley ldquoMechanisms of HIV-associated lymphocyte apoptosis 2010rdquo Cell Death and Diseasevol 1 no 11 article e99 2010
[70] A M Loyola S V Cardoso G S Lisa et al ldquoApoptosis inepithelial cells of apical radicular cystsrdquo International Endodon-tic Journal vol 38 no 7 pp 465ndash469 2005
[71] T Suzuki H Kumamoto K Kunimori andKOoya ldquoImmuno-histochemical analysis of apoptosis-related factors in liningepithelium of radicular cystsrdquo Journal of Oral Pathology andMedicine vol 34 no 1 pp 46ndash52 2005
[72] C A Martins E R C Rivero R M Dufloth C P Figueiredoand D S C Vieira ldquoImmunohistochemical detection of factorsrelated to cellular proliferation and apoptosis in radicular anddentigerous cystsrdquo Journal of Endodontics vol 37 no 1 pp 36ndash39 2011
[73] E Kichi Y Enokiya T Muramatsu et al ldquoCell proliferationapoptosis and apoptosis-related factors in odontogenic kerato-cysts and in dentigerous cystsrdquo Journal of Oral Pathology andMedicine vol 34 no 5 pp 280ndash286 2005
[74] A Piattelli M Fioroni and C Rubini ldquoDifferentiation ofodontogenic keratocysts from other odontogenic cysts by theexpression of bcl-2 immunoreactivityrdquo Oral Oncology vol 34no 5 pp 404ndash407 1998
[75] G C P Mateus G H D S P Lanza P H R deMoura H A deMarigo and M C R Horta ldquoCell proliferation and apoptosisin keratocystic odontogenic tumorsrdquo Medicina Oral PatologiaOral y Cirugia Bucal vol 13 no 11 pp E697ndashE702 2008
[76] L Artese A Piattelli C Rubini et al ldquop16 expression inodontogenic tumorsrdquo Tumori vol 94 no 5 pp 718ndash723 2008
[77] L Lo Muzio S Staibano G Pannone et al ldquoExpression of cellcycle and apoptosis-related proteins in sporadic odontogenickeratocysts and odontogenic keratocysts associated with thenevoid basal cell carcinoma syndromerdquo Journal of DentalResearch vol 78 no 7 pp 1345ndash1353 1999
10 Journal of Oral Diseases
[78] D K Kim S G Ahn J Kim and J H Yoon ldquoComparativeKi-67 expression and apoptosis in the odontogenic keratocystassociated with or without an impacted tooth in addition tounilocular and multilocular varietiesrdquo Yonsei Medical Journalvol 44 no 5 pp 841ndash846 2003
[79] M Andric B Dozic B Popovic et al ldquoSurvivin expression inodontogenic keratocysts and correlation with cytomegalovirusinfectionrdquo Oral Diseases vol 16 no 2 pp 156ndash159 2010
[80] I R H Kramer J J Pindborg and M ShearWHOHistologicalTyping of Odontogenic Tumours Springer Berlin Germany1992
[81] H Kumamoto and K Ooya ldquoDetection of mitochondria-mediated apoptosis signaling molecules in ameloblastomasrdquoJournal of Oral Pathology and Medicine vol 34 no 9 pp 565ndash572 2005
[82] H Kumamoto and K Ooya ldquoImmunohistochemical detectionof BH3-only proteins in ameloblastic tumorsrdquo Oral Diseasesvol 14 no 6 pp 550ndash555 2008
[83] H Kumamoto and K Ooya ldquoExpression of tumor necrosisfactor120572 TNF-related apoptosis-inducing ligand and their asso-ciated molecules in ameloblastomasrdquo Journal of Oral Pathologyand Medicine vol 34 no 5 pp 287ndash294 2005
[84] H Kumamoto K Kimi and K Ooya ldquoImmunohistochemicalanalysis of apoptosis-related factors (Fas Fas ligand caspase-3and single-stranded DNA) in ameloblastomasrdquo Journal of OralPathology and Medicine vol 30 no 10 pp 596ndash602 2001
[85] T E Carneiro S A Marinho F D Verli A T M Mesquita NL Lima and J L Miranda ldquoOral squamous papilloma clinicalhistologic and immunohistochemical analysesrdquo Journal of oralscience vol 51 no 3 pp 367ndash372 2009
[86] T Yamaguchi M Shindoh A Amemiya et al ldquoDetectionof human papillomavirus type 2 related sequence in oralpapillomardquo Analytical Cellular Pathology vol 16 no 3 pp 125ndash130 1998
[87] J H Main and M Pavone ldquoActinic cheilitis and carcinoma ofthe liprdquo Journal of Canadian Dental Association vol 60 no 2pp 113ndash116 1994
[88] A Martınez U Brethauer I G Rojas et al ldquoExpression ofapoptotic and cell proliferation regulatory proteins in actiniccheilitisrdquo Journal of Oral Pathology and Medicine vol 34 no5 pp 257ndash262 2005
[89] M A Birchall C MWinterford D J Allan and B V HarmonldquoApoptosis in normal epithelium premalignant and malignantlesions of the oropharynx and oral cavity a preliminary studyrdquoEuropean Journal of Cancer B vol 31 no 6 pp 380ndash383 1995
[90] N Tanda S Mori K Saito K Ikawa and S SakamotoldquoExpression of apoptotic signaling proteins in leukoplakia andoral lichen planus quantitative and topographical studiesrdquoJournal of Oral Pathology and Medicine vol 29 no 8 pp 385ndash393 2000
[91] G Kovesi and B Szende ldquoProgression of the leukoplakia isassociated to changes in apoptotic and mitotic index as well asin p53 and Ki-67 expressionrdquo Oncology vol 46 no 4 pp 333ndash338 2002
[92] H Tsuzuki S Fujieda H Sunaga N Narita M Tokuriki andH Saito ldquoExpression of p27 and apoptosis in oral leukoplakiardquoAnticancer Research vol 23 no 2 pp 1265ndash1270 2003
[93] E Chrysomali J S Greenspan N Dekker D Greenspanand J A Regezi ldquoApoptosis-associated proteins in oral hairyleukoplakiardquo Oral Diseases vol 2 no 4 pp 279ndash284 1996
[94] S H Kaufmann andG J Gores ldquoApoptosis in cancer cause andcurerdquo BioEssays vol 22 pp 1007ndash1017 2000
[95] S Ghavami M Hashemi S R Ande et al ldquoApoptosis andcancer mutations within caspase genesrdquo Journal of MedicalGenetics vol 46 no 8 pp 497ndash510 2009
[96] C M Coutinho-Camillo S V Lourenco I N NishimotoL P Kowalski and F A Soares ldquoCaspase expression in oralsquamous cell carcinomardquo Head and Neck vol 33 no 8 pp1191ndash1198 2011
[97] P J Polverini and J E Nor ldquoApoptosis and predisposition tooral cancerrdquo Critical Reviews in Oral Biology and Medicine vol10 no 2 pp 139ndash152 1999
[98] M Sulkowska W Famulski S Sulkowski et al ldquoCorrelationbetween Bcl-2 protein expression and some clinicopathologicalfeatures of oral squamous cell carcinomardquo Polish Journal ofPathology vol 54 no 1 pp 49ndash52 2003
[99] L L Loro O K Vintermyr P G Liavaag R Jonsson and A CJohannessen ldquoOral squamous cell carcinoma is associated withdecreased bcl-2bax expression ratio and increased apoptosisrdquoHuman Pathology vol 30 no 9 pp 1097ndash1105 1999
[100] M Baltaziak M KodaM Barwijuk-Machała et al ldquoThe role ofBak expression in apoptosis of the oral squamous cell carcinoma(OSCC) and metastases to lymph nodes (LNMs)rdquo AnnalesAcademiae Medicae Bialostocensis vol 49 pp 14ndash15 2004
[101] J C de Vicente L M J Gutierrez A H Zapatero M FF Forcelledo G Hernandez-Vallejo and J S Lopez ArranzldquoPrognostic significance of p53 expression in oral squamous cellcarcinoma without neck node metastasesrdquo Head and Neck vol26 no 1 pp 22ndash30 2004
[102] M A Gonzalez-Moles P Galindo J Gutierrez-Fernandez etal ldquoP53 protein expression in oral squamous cell carcinomasurvival analysisrdquo Anticancer Research vol 21 no 4 pp 2889ndash2894 2001
[103] S Kannan G Jagadeesh Chandran K Raveendran Pillai et alldquoExpression of p53 in leukoplakia and squamous cell carcinomaof the oral mucosa correlation with expression of Ki67rdquo Journalof Clinical Pathology vol 49 no 3 pp M170ndashM175 1996
[104] J Y Koh N P Cho G Kong J D Lee and K Yoon ldquop53mutations and human papillomavirus DNA in oral squamouscell carcinoma correlation with apoptosisrdquo British Journal ofCancer vol 78 no 3 pp 354ndash359 1998
[105] L LoMuzio G Pannone S Staibano et al ldquoSurvivin expressionin oral squamous cell carcinomardquo British Journal of Cancer vol89 no 12 pp 2244ndash2248 2003
[106] Y Jinbu K Tsukinoki N Miyagi et al ldquoExpression of survivinin oral squamous cell carcinomardquo Oral Med Pathol vol 11 pp41ndash44 2006
[107] C Jane A V Nerurkar N V Shirsat R B DeshpandeA D Amrapurkar and F R Karjodkar ldquoIncreased survivinexpression in high-grade oral squamous cell carcinoma a studyin Indian tobacco chewersrdquo Journal of Oral Pathology andMedicine vol 35 no 10 pp 595ndash601 2006
[108] Y-H Kim S-M Kim Y-K Kim S-P Hong M-J Kim andH Myoung ldquoEvaluation of survivin as a prognostic marker inoral squamous cell carcinomardquo Journal of Oral Pathology andMedicine vol 39 no 5 pp 368ndash375 2010
[109] N G Nikitakis J J Sauk and S I Papanicolaou ldquoThe role ofapoptosis in oral disease mechanisms aberrations in neoplas-tic autoimmune infectious hematologic and developmentaldiseases and therapeutic opportunitiesrdquo Oral Surgery OralMedicine Oral Pathology Oral Radiology and Endodontics vol97 no 4 pp 476ndash490 2004
[110] L L Loro O K Vintermyr A C Johannessen P G Liavaagand R Jonsson ldquoSuppression of Fas receptor and negative
Journal of Oral Diseases 11
correlation of Fas ligand with differentiation and apoptosis inoral squamous cell carcinomardquo Journal of Oral Pathology andMedicine vol 28 no 2 pp 82ndash87 1999
[111] N H Al-Rawi H Omer and S Al Kawas ldquoImmunohistochem-ical analysis of P53 and bcl-2 in benign and malignant salivaryglands tumorsrdquo Journal of Oral Pathology and Medicine vol 39no 1 pp 48ndash55 2010
[112] ANordkvist E Roijer G Bang et al ldquoExpression andmutationpatterns of p53 in benign andmalignant salivary gland tumorsrdquoInternational Journal of Oncology vol 16 no 3 pp 477ndash4832000
[113] V J Karja K J Syrjanen A-K Kurvinen and S M SyrjanenldquoExpression and mutations of p53 in salivary gland tumoursrdquoJournal of Oral Pathology and Medicine vol 26 no 5 pp 217ndash223 1997
[114] M Yanezez I Roa M Garcıa G Ibacache and M VillasecaldquoGene Bcl-2 protein expression in salivary gland tumorsrdquoRevista Medica de Chile vol 127 no 2 pp 139ndash142 1999
[115] L Jia R L Esguerra X Tang et al ldquoPrognostic value ofapoptosis and apoptosis-associated proteins in salivary glandadenoid cystic carcinomardquo Pathology International vol 54 no4 pp 217ndash223 2004
[116] Y Soini U Tormanen and P Paakko ldquoApoptosis is inverselyrelated to bcl-2 but not to bax expression in salivary glandtumoursrdquo Histopathology vol 32 no 1 pp 28ndash34 1998
[117] R M Nagler H Kerner S Ben-Eliezer I Minkov and O Ben-Itzhak ldquoPrognostic role of apoptotic Bcl-2 c-erbB-2 and p53tumor markers in salivary gland malignanciesrdquo Oncology vol64 no 4 pp 389ndash398 2003
state of the body A dysfunctional apoptotic system canlead to either excessive removal or prolonged survival ofcells and thus dysregulated apoptosis is implicated in patho-genesis of a variety of diseases including oral patholo-gies The present review attempts to summarise and high-light the role and significance of apoptosis in various oraldiseases
2 Classification of Oral Diseases
(1) Reactive lesions
(i) Pyogenic granuloma(ii) Giant cell granuloma
(2) Inflammatory diseases
(i) Recurrent aphthous stomatitis (may fall intomore than one category)
311 Apoptosis and Pyogenic Granuloma Cells in multicel-lular organisms are inflicted with a variety of challengesto which they react by regeneration hyperplasia dysplasiahypertrophy atrophy or metaplasia depending on the natureof the challenge These modes of cellular adaptability involvemodulation of the balance between cell proliferation and celldeath [7] Pyogenic granuloma (PG) is one of the inflamma-tory hyperplasias seen in the oral cavity which may arise inresponse to various stimuli such as low-grade local irritationtraumatic injury or hormonal factors [8] Lower ISTR (in situ31015840-tailing reaction) labeling indices and more frequent Bcl-2Bax expression in PG than granulation tissue and capillaryhemangioma suggested that the low apoptotic rate in PG isclosely related to its characteristic rapid growth [9] It has alsobeen found that in pregnancy tumor female sex hormonesnot only enhance the expression of angiogenic factors but alsodecrease apoptosis of granuloma cells to extend angiogeniceffect [10] VEGF alone or in combination with Ang-2 couldprotect microvessels from apoptosis while Ang-2 alone hadno effectTherefore lack of VEGF is associated with apoptosisof endothelial cells and regression of granuloma [11]
312 Apoptosis and Giant Cell Granuloma Central giant celllesion (CGCL) and peripheral giant cell lesion (PGCL) ofthe jaws are characterized by multinucleated osteoclast-likegiant cells in a background of mononuclear cells [12 13]Pammer et al [13] demonstrated strong expression of Baxand Bak weak positivity for Bcl-2 and moderate positivityfor Bcl-x in majority of giant cells in PGCL and lesionscontaining osteoclast-like giant cells whereas only scatteredmononuclear cells were positive for Bax Bak and Bcl-2 Alsofrequency of apoptotic nuclei was 18 times higher in giantcells than in mononuclear cells suggesting that giant cellsof bone and soft tissue tumors are reactive cell forms andare not of neoplastic origin Both CGCL and PGCL showedincreased expression of Bax and Bcl-2 mRNA PGCL showeda higher apoptotic index (ratio BaxBcl-2) than CGCL alsoconfirmed by TUNEL analysis which might be associatedwith the different clinical behavior of CGCL and PGCL[12]
32 Apoptosis and Inflammatory Diseases
321 Apoptosis and Recurrent Aphthous Ulceration Recur-rent aphthous ulceration (RAU) is a common inflammatorycondition of the oral mucosa predominantly affecting liningoral mucosa [7] Recurrent aphthous like ulceration is acardinal feature of Behcetrsquos syndrome and is consistentlyassociated with it [14] Ultrastructurally normal oral mucosaof patients with RAU or Behcetrsquos syndrome revealed degen-erated apoptotic prickle cells and it was speculated that theonset of aphthous ulceration is closely related to phagocytosisof these apoptotic cells by intraepithelial mononuclear cells[15] RAU induces p53 immunoexpression which might berelated to its aetiopathogenesis [16]
Journal of Oral Diseases 3
322 Apoptosis and Diseases of Periodontium Periodontaldisease is an acute or chronic inflammatory condition whichdevelops as a result of imbalance in the equilibrium betweenthe host defence andmicrobial agents resulting in destructionof tooth-supporting tissue leading to mobility and tooth lossTUNEL positive cells positive staining with active caspase-3 Fas FasL p53 and chromatin condensation was found inthe inflammatory infiltrates of periodontitis patients whereasBcl-2 positivity was found in both periodontitis patients andhealthy controls thus concluding that apoptotic mechanismcould be implicated in the inflammatory process associatedwith periodontitis [17] A greater number of apoptotic ker-atinocytes than proliferative ones are found in periodon-titis patients only in the most apical part of the sulcuscompared to those with gingivitis [18] Monocytes are themost lysis-sensitive leukocytes for A actinomycetemcomitansleukotoxin which depends on caspase 1-activation [19] It isalso evidenced that live P gingivalis can induce significantapoptosis in primary human gingival epithelial cells between12 and 24 hours of challenge via gingipains dependentmechanism [20] Hydrogen sulfide can induce apoptosis ingingival epithelial cells and human gingival fibroblast inthe oral cavity which may cause a periodontal condition[21] Neutrophils when combined in a P gingivalis challengeassay of epithelial cells prevent epithelial cell apoptosis byphagocytosing P gingivalis and also protect the host fromthe harmful effects of its microbial proteases [22] It has alsobeen analysed that the increased fibroblast proliferation anda simultaneous decrease in apoptosis contribute to gingivalovergrowth [23]
33 Apoptosis and Immune-Mediated Diseases
331 Apoptosis and Oral Lichen Planus The hallmarkhistopathologic feature of lichen planus (LP) is the degen-eration of the basal layer of the epithelium Eosinophilicglobular bodies also known as colloid hyaline cytoid orCivatte bodies are also characteristic features of LP seen inthe basal layer and upper connective tissue and have beeninterpreted as degenerative keratinocytes Damage to thebasal layer appears to involve apoptosis as an early event [24]The following mechanisms are proposed for keratinocyteapoptosis
(1) T-cell-secreted TNF-120572 binding to TNF-120572 R1 receptoron keratinocyte surface
(2) T-cell surface CD95L (Fas ligand) binding to CD95(Fas) on the keratinocyte surface
(3) T-cell-secreted granzyme B entering the keratinocytevia perforin induced membrane pores
All these mechanisms activate caspase cascade resultingin keratinocyte apoptosis On the contrary reduced or absentapoptotic rate in inflammatory cells has been thought tocontribute to development of OLP [25]
One of the studies demonstrated that caspases 2 and 12were expressed in all samples and caspase-8 was expressed inmost of the samples of atrophic lichen planus suggesting theimportance of endoplasmic reticulum (ER) stress in inducing
apoptosis in OLPs However the activation of death receptorsin OLP cannot be ruled out [26] Increased apoptosis maycause a decrease in epithelial thickness reflected in the activityof the lesion It was found that apoptosis in the erosiveOLP was significantly more intense than in the reticulartype and both forms of OLP presented more apoptosis thanthe healthy oral mucosa [27] It has been demonstratedthat increased numbers of apoptosis were detected in OLPespecially in association with lymphocytic infiltration andhematoxylin-eosin staining being more sensitive in detectinghigher number of apoptotic nuclei than in situ end labeling[28] Expression of cell proliferation proteins like PCNAand apoptotic proteins like Bcl-2 and Bax was found to bealtered in OLP as seen in epithelial dysplasia suggestingtheir potential for malignant transformation [29] TUNELand caspase-3 expression showed absence or low rate ofapoptosis in inflammatory cells in OLP thus contributingto the persistence of the inflammation and favouring cancerdevelopment [30] Apoptosis in OLP seems to be correlatedwith granzyme B release while in oral cGVHD perforinseems to bemore important suggesting that subtle differencesseem to exist in their pathogenetic mechanisms [31]
332 Apoptosis and Erythema Multiforme Erythema multi-forme is a distinct dermatologic hypersensitivity pathologycharacterized by cutaneous or mucous lesions and eventuallyit can also involve both In their more severe forms theyappear with occasional visceral involvements It includeswide range of clinical patternsmdashEM minor EM majorStevens Johnson syndrome and toxic epidermal necrolysis[32] Cell death in EM is at least in part due to apoptosiswhich may be related to an altered expression of apoptosis-regulating proteins like p53 and Bcl-2 family proteins andactivation of FasFas-ligand system [33] ELISA and in vitroanalysis showed that sFasL secreted by PBMCs not ker-atinocytes plays a crucial role in the keratinocyte apoptosisand pathogenetic mechanism of TEN and SJS and serumsFasL level may be a good indicator for the early diagnosisof TEN and SJS [34] It has also been found that perforinmediates apoptosis in the pathogenesis of the epidermal cellchanges in SJS [35]
333 Apoptosis and Lupus Erythematosus Systemic lupuserythematosus (SLE) and discoid lupus erythematosus (DLE)are autoimmune diseases manifesting as erythematous orulcerative lesions with white striae radiating from the mar-gins [7] CD95 mutations are linked with loss of regulation ofB lymphocytes which predisposes to systemic autoimmunityincluding SLE [36] Autoantigens in SLE become clustered inand on the surface blebs of apoptotic cells and these cells playa central role in tolerizing B cells andT cells andmay drive theautoimmune response in systemic autoimmune disease [37]SLE is characterized by imbalance redox state which in turnis related to intracellular levels of glutathione and controlledproduction of reactive oxygen species and alteration in theintracellular redox environment of cells are critical for cellularimmune dysfunction activation of apoptotic enzymes andapoptosis [38] It has also been demonstrated that elevatedendothelial cell apoptosis strongly correlates with markedly
4 Journal of Oral Diseases
abnormal vascular function and elevated tissue factor levelsandmay represent an importantmechanism for developmentof atherothrombosis in SLE [39]
334 Apoptosis and Pemphigus Vulgaris Pemphigus is agroup of autoimmune blistering diseases characterized byloss of keratinocyte cell adhesion that leads to clinical blisterformation Induction of apoptosis or of proapoptotic proteinsby pemphigus IgGmay be (i) part of themechanism bywhichsera and IgG induce acantholysis or (ii) a consequence of lossof adhesion (anoikis) and a result of acantholysis [40] Fasligand levels are markedly increased in sera from untreatedpemphigus patients which is suggesting that FasFas lig-and cell death pathway plays amajor role in anoikis as seen inpemphigus [41] Hoechst 33342 staining andRT-PCR analysisshowed that apoptosis may be associated with acantholysisof pemphigus lesional epidermis and may play an importantrole in the pathogenesis of pemphigus [42] Apoptosis isobserved in the perilesional normal appearing tissue sug-gesting that it is an early phenomenon Also the process ofapoptosis may cause exacerbation or speeding of the bullaformation [43] But whether apoptosis is really essential foracantholysis in pemphigus is not clear Immunofluorescenceanalysis confirmed that PV IgG autoantibodies promoteapoptosis in HaCaT keratinocytes characterized by caspase-3activation Bcl-2 depletion and Bax expression [44]
335 Apoptosis and Epidermolysis Bullosa Epidermolysisbullosa is a hereditary vesiculobullous disease characterizedby blistering of the skin and oral mucosa due to basalkeratinocyte fragility [7] Experiment using cellular model ofEBS showed thatHaCaT cells were susceptible to apoptosis byactivation of caspases 3 and 8 but not caspase-9 or caspase-12 Moreover TNF-120572 release and the subsequent activationof the TNF-120572 receptor by an autocrineparacrine pathwaylink protein aggregates to cell death in this keratinocyteEBS cellular model Also susceptibility of keratinocytes tocaspase-8-mediated apoptosis is increased in mutated K14because of impairment of the cytoprotective mechanismmediated by K14-TRADD interaction [45]
336 Apoptosis and Oral Graft-versus-Host Diseases Graft-versus-host disease (GVHD) is characterized by an immune-mediated attack by donor immune cells against variousrecipient host cells and tissues Although donor and recip-ient are matched at major histocompatibility loci prior totransplantation GVHD occurs because differences exist atminor histocompatibility loci Programmed cell death orapoptosis has been evidenced as major constituent in thepathogenesis of GVHD Oral involvementmay be seen in 33ndash75 of patients who develop acute GVHD and in up to 80of patients affected by chronic GVHD making these lesionsuseful as a highly predictive index for the presence of systemicdisease The oral lesions of GVHD are clinically and histo-logically lichenoid in nature [46] CTL mediated apoptoticpathway predominates in GVHD Initiation can occur eitherwhen virus-specific cytotoxic T lymphocytes (CTL) bind totarget cells and release granzymes into the cells or when CTL
bind and activate the TNF family of receptors such as the Fas-receptor or TRAIL-receptor [46ndash48] Caspases and severalintracellular proteases participate in propagating and actuat-ing the apoptotic death signal through a proteolytic cleavagecascade [49 50] Phosphorylation pathways regulate signaltransduction cascades [51] However experimental murinemodels of acute GVHD demonstrated that apoptosis can beinduced even in the absence of immune cells suggestingexistence of an additional mechanism for target cell injury[52]
337 Apoptosis and Sjogrenrsquos Syndrome Sjogrenrsquos syndrome(SS) is an autoimmune disease characterized by diffuselymphoid cell infiltrates in the salivary and lacrimal glandsresulting in symptoms of dry mouth and eyes [53] Threeaspects of apoptosis are related to SS (i) defective apopto-sis could lead to lymphoid cell accumulation and chronicinflammation in exocrine glands (ii) increased apoptosis ofepithelial cells might explain the loss of secreting epitheliumand (iii) orderly destruction of cellular components mightinduce autoantibody production [54] Apoptosis of the acinarand ductal epithelial cells of the salivary and lacrimal glandsmay be induced by either CTL through the release perforinand granzyme B or the interaction of Fas ligand expressedby T lymphocytes with Fas on epithelial cells [55] On thecontrary others believed that Fas-induced apoptosis amongSS salivary glands is a rare event despite their abundantexpression since infiltratingmononuclear cells seem to escapeapoptosis resulting in foci of inflammatory cells [56] 120 kDa120572-Fodrin is an important autoantigen in the developmentof SS in animal models and SS patients Anti-Fas antibody-induced apoptosis and an increase in the activities of calpainand caspases may be involved in the progression of 120572-fodrin proteolysis and tissue destruction in the developmentof SS [53] In vitro analysis demonstrated that apoptosistriggered by anti-Ro and anti-La could be responsible for theimpairment of the secretory function in the salivary glands[57]
34 Apoptosis and Virus Associated Diseases Various typesof viruses have been involved in the pathogenesis of dif-ferent oral lesions the commonest being herpes simplexvirus (HSV) human papillomaviruses (HPV) and humanimmunodeficiency virus (HIV) Virus infected cells can oftenbe recognized and destroyed by apoptotic processes initiatedby either CTL or certain cytokines Many viruses directlyinduce apoptosis during infection which is at least partiallyresponsible for the various viral pathologies Many viruseshave evolved with multiple distinct mechanisms to blockthe premature apoptosis of infected cells either facilitatingthe maintenance of persistent infection or prolonging thesurvival of lytically infected cells such that the production ofprogeny virus is maximized [58] Examples include blockageof apoptosis by viral BCL-2 (vBCL-2) homologues [59] uti-lization of the phosphatidylinositol 3-kinase-Akt signallingpathway [60] or suppression of inducers of apoptosis suchas p53 [61]
HSV infection triggers apoptosis in infected cells How-ever proteins synthesized later in infected cells prevent
Journal of Oral Diseases 5
apoptotic cell death from ensuingThis apoptoticmodulationhas a role in the development of herpetic disease [62] HSV-1-induced apoptosis of immature dendritic cells is associatedwith downregulation of the cellular FLICE-inhibitory protein(c-FLIP) in a proteasome-independent manner [63] HSV-1triggers apoptosis in CNS neurons and causes encephalitis inadult subjects [64] HSV-1 enhances apoptosis via expressionof both Fas and Fas ligand on the surface of neonatalneutrophils [65]
High risk HPV oncoproteins E6 E7 and E5 can mod-ulate host mediated apoptosis by inhibiting death receptorsignaling and thus regulate the survival of infected cells [66]HPV E6 proteins inhibit apoptosis in both p53-dependentand p53-independent manners HPV-18 E6 inhibits Bak-induced apoptosis in differentiating keratinocytes in whichHPV replicates It was also suggested that Bak is probably thefirst naturally occurring target of ubiquitin ligase E6AP [67]
HIV infection usually leads to progressive immunod-eficiency and loss of immune competence associated withdeclines in both the functionality and the number of CD4+lymphocytes which in turn is related to various viral andimmunological processes Proposed virus-mediated mech-anisms include toxicity caused by accumulation of uninte-grated viral DNA alteration in membrane permeability dueto budding of viral particles and terminal differentiationAmong the immunological mechanisms are killing by spe-cific CTL and signaling through the CD4 molecule leadingto CD4+ lymphocytes apoptosis [68] Apoptosis in HIV maybe stimulated by environmental stress toxins and removalof growth factors and may be mediated by one of thesedeath inducing ligands TNF FasL and TRAIL [69] Manyof the proteins that are encoded by the HIV genome havebeen found to have pro- andor antiapoptotic qualities HIVsurface glycoprotein gp120 cross-links CD4 and primes cellsfor apoptosis HIV-1 can also induce apoptosis ldquofrom withinrdquovia expression of certain viral genes such as tat nef vpu andvpr [68 69]
35 Apoptosis and Benign Entities
351 Apoptosis and Benign Odontogenic Cysts and Tumors
(1) Apoptosis and RadicularApical Cyst Radicular cysts arethe most common cystic lesions of the jaws and representa periapical inflammatory disease evoked by infected andnecrotic dental pulp Apoptosis was found to be alwayspresent in the epithelium of the apical radicular cyst Higherapoptotic index (AI) and bcl-2 index (bcl-2I) were found inlesions with atrophic compared to hyperplastic epitheliumbut the difference was statistically insignificant However apositive and significant correlation was found between AIand bcl-2I [70] Epithelium of radicular and residual cystsshowed expression of apoptosis related factors like ssDNAp53 Bax Bcl-2 caspase-3 Fas Fas-L and Ki-67 antigensuggesting their role in the pathophysiologic activity ofperiapical inflammatory lesions Such factors may be affectedby the structure of lining epithelium and the degree ofinflammatory change since Ki-67 and ssDNA reactivity inRCs with intense inflammatory reactions or with thick lining
epithelium were significantly stronger than those RCs withless inflammation or with thin lining [71] Caspase-3 andKi-67 expression was significant in hyperplastic epitheliumrelated to intense inflammation whereas Bcl-2 expressionwas significantly higher in atrophic epithelium of DCs thanRCs suggesting that although they may have different patho-genetic mechanism they have similar biological behavior inthe presence of intense inflammatory infiltrate [72]
(2) Apoptosis and Dentigerous Cyst The epithelial lining ofDCs has shown TUNEL Ki-67 and p53 positivity but theexpression was weak as compared to OKCs indicating thatapoptosis is involved in cyst formation and maintainingthe regular thickness of the lining epithelium in DCs [73]Bcl-2 positivity was significantly higher in atrophic epithe-lium of DCs than that of RCs suggesting that presence ofinflammation inhibits the Bcl-2 expression and both cystshave similar biological behavior in the presence of intenseinflammatory infiltrate [72] whereas other demonstrated thatBcl-2 expression was almost completely negative in DCs andRCs compared to OKCs [74]
(3) Apoptosis and Odontogenic KeratocystKeratocystic Odon-togenic Tumor Keratocystic odontogenic tumor (KCOT)also known as odontogenic keratocyst (OKC) was recentlyclassified as a benign neoplasia due to the aggressive clinicalbehavior The proliferation index and apoptotic index werefound to be higher and with distinct pattern in both sporadicand nevoid basal cell carcinoma syndrome (NBCCS) KCOTscompared to DCs reflecting its high cell turnover andreinforcing its classification as an odontogenic tumor [75]Lack of p16 expression in KCOT compared to strong ormoderate p16 expression in RCs and follicular cysts couldbe related to the increased aggressive behavior invasivenessand high frequency of recurrences found in KCOT [76]Overexpression of cyclin Dl and p53 in syndromic OKCscould be considered as hallmark of a mutated cellular phe-notype and more aggressive clinical behaviour compared tosporadic KCOTs which were negative for these oncoproteins[77] Strong Bcl-2 overexpression in OKCs suggests its rolein extension of cell survival leading to the peculiar aggressivegrowth pattern and can be useful to differentiate OKC fromother odontogenic cysts [74] TUNEL positive cells wereobserved in the surface layers of OKCs whereas no positivitywas seen in the basal or intermediate layers of OKCs andDCs Also Ki67-positive ratio and p53-positive ratio in theintermediate layer were the highest in OKCs and Bcl-2-positive cells were discernible exclusively in the basal layerof OKCs signifying that subsequently OKCs are seen ascystic lesions but not as tumor masses [73] There is nosignificant difference in proliferative activity and apoptosisin OKCs associated with or without impacted teeth orbetween the unilocular ormultilocular variants [78] Survivinimmunoexpression was positive in all cases of OKCs while allperiapical cysts were negative suggesting its contribution toviolent behavior of OKCs [79]
(4) Apoptosis and Ameloblastomas Ameloblastoma isthe most frequently encountered tumor arising from
6 Journal of Oral Diseases
odontogenic epithelium and is characterized by a benign butlocally invasive behavior with a high risk of recurrence [80]
RT-PCR and IHC showed expression of cytochrome cAPAF-1 caspase-9 and AIF in tooth germs and benign andmalignant ameloblastomas suggesting that themitochondria-mediated apoptotic pathway has a role in apoptotic celldeath of normal and neoplastic odontogenic epithelium andmight be involved in oncogenesis cytodifferentiation andmalignant transformation of odontogenic epithelium [81]
Granular cells basal cells desmoplastic ameloblastomasand ameloblastic carcinomas showed immunoreactivity forthe BH3-only proteins (Bid Bim Bad Noxa and Puma)whereas keratinising cells of acanthomatous ameloblastomasshowed no reactivity suggesting that these proteins mightbe involved in tumor cell differentiation of ameloblastomas[82] TNF-120572 TRAIL and their receptors were also found tobe expressed in tooth germs and ameloblastomas provingtheir role in cytodifferentiation of odontogenic epitheliumand tissue structuring of ameloblastomas [83] Similarlyexpression of Fas FasL caspase-3 and ssDNA has also beendemonstrated in various patterns in tooth germs and benignand malignant ameloblastomas [84]
352 Apoptosis and Benign Epithelial Tumor
(1) Apoptosis and Squamous PapillomaOral squamous papil-loma (OSP) is a frequent benign tumorous lesion associatedwith HPV OSP consists of proliferation of the stratifiedsquamous epithelium resulting in a papillary or verrucousexophytic mass and has got site predilection for the tongueand soft palate but any surface of the oral cavity can beaffected [85 86] Carneiro et al performed immunohisto-chemical assay on 12 OSP cases utilizing BP53-12 and Pab240antibodies for p53 protein and found that immunostainingfor protein p53 was primarily negative or weakly positivein all cases (in all epithelial layers) except one case whichindicates the benign nature of the lesions evidenced by theirslow development and less chances of becoming malignantIntense staining in one slide for both immunomarkers in allthe epithelial layers could be attributed to the presence ofvirus with high oncogenic potential (HPV 16 and 18) or tothe presence of coexisting external factors [85]
36 Apoptosis and Premalignant and Malignant Entities
361 Apoptosis and Actinic Cheilitis Actinic cheilitis (AC) isa common condition caused by damage to the lips throughexposure to sunlight and has the potential to undergomalignant transformation into squamous cell carcinoma [87]Overexpression of p53 was found in AC as compared tonormal lip and oral mucosa Bcl-2 expression was higherin AC than in oral mucosa but it was significantly reducedas compared with normal lip Thus it was suggested thatDNA-damaged cells by UV radiation in AC are eliminatedby apoptosis Also both p53 and bcl-2 play an important rolein regulating malignant transformation in AC [88]
362 Apoptosis and Oral Leukoplakia It has been sug-gested that a change in apoptosis accompanies the onset
of invasion in a premalignant lesion of the human oralcavity and oropharynx AI increased progressively fromnormal to carcinoma in situ (CIS) but fell in SCC withmaximum apoptotic index (AI) mitotic index (MI) ratioin CIS The position of apoptotic bodies was localised tothe deepest layers in normal and dysplastic epithelia butbecame generalised in CIS and SCC [89] Greater expressionof oncoproteins MDM2 and Bcl-2 was seen in leukoplakiawith altered keratinocyte maturation than OLP case whereasexpression of wt-p53 and p21 was higher in OLP compared toleukoplakia cases In spite of divergent outcome of apoptoticsignalling proteins no significant difference in the number ofapoptotic epithelial cells was observed between leukoplakiaand OLP cases [90] Increased mitotic apoptotic and Ki-67 index indicate unfavourable prognosis of leukoplakia [91]Abundance of p27 expression in oral leukoplakia may beassociated with inhibition of cell proliferation leading toapoptosis of premalignant tumor cells thus preventing tumorprogression [92] It is hypothesised that the antiapoptoticability of Epstein-Barr virus (EBV) may result in alteredexpression of apoptosis-associated proteins in oral hairyleukoplakia Except p53 which appears to be overexpressedthere is only slight alteration in immunoexpression of otherapoptosis-associated proteins in OHL [93]
363 Apoptosis and Oral Squamous Cell Carcinoma Theaccumulation of neoplastic cells can occur through enhancedproliferation diminished cell turnover or a combination ofboth processes Tumor cells from a wide variety of humancancers have been shown to exhibit increased survival andresistance to apoptosis [94] There are two major ways thatcould downregulate cancer cell apoptosis (1) somatic andnonsomatic mutation and loss of expression of proapoptoticmolecules and (2) overexpression of apoptosis inhibitorymolecules Mutations within caspase family proteases are notuncommon in malignancies [95] Caspase-7 proved to bean independent prognosticator and predictor of locoregionalrecurrence in patients of OSCC [96] Several alterations thatinhibit both the death receptor and mitochondrial pathwaysvia caspases have also been identified including overexpres-sion of IAPs activation of PI3k or Akt and posttranslationalmodifications of caspases [94]
In pathological settings Bcl-2 gene family appears toact synergistically with oncogenes and tumor suppressorgenes [97] Positive Bcl-2 expression is associated with highertumor grading higher tumor mitotic index higher index ofatypical mitoses and microfocal pattern of tumor invasivemargins [98] In OSCC compared with oral epitheliumthere is a decreased Bcl-2 expression a lowered Bcl-2Baxratio and increased apoptosis Expression of Bax correlatedwith histological tumor grading in OSCC [99] whereasothers found that expression of Bak may be useful for bettercharacterizing and predicting the prognosis of OSCC [100]
Aberrations of the p53 gene and overexpression of its pro-tein are widely recognized markers of malignancy includingOSCC It was found that there is a negative correlation of p53immunoexpression with histologic grade of differentiationIn patients without neck node metastases p53 showed astrong correlation with survival [101] On the contrary
Journal of Oral Diseases 7
another study showed that expression of p53 protein did notbehave as amarker of prognostic value in patients withOSCC[102]
As cancer is characterized by uncontrolled cell prolif-eration markers of proliferation such as Ki67 and PCNAhave been studied extensively in neoplastic lesions Expres-sion of both p53 and Ki67 correlated significantly with thehistopathological stage of the tumor However expression ofp53 was not correlated with that of Ki67 [103]
HPV infection andor p53 mutations are implicated incarcinogenesis of oral SCC but are not mutually exclusiveevents Moreover decrease in apoptosis is more closelyrelated to p53 mutation than HPV infection [104]
Survivin has got a versatile role in modulating celldivision and apoptosis in cancer Low survivin expressioncorrelated statistically significantly with better survival ratesbut not with age sex tumor size the presence of lymphnode or distant metastases [105] Survivin was found tobe preferentially expressed in nonadvanced nonmetastaticand chemotherapy-sensitive OSCC [106] On the contraryincreased expression of survivin was found in high-gradetumors suggesting its contribution to apoptosis resistancein response to therapy [107] Also significant correlationbetween survivin expression lymph node metastasis andproliferation was revealed but not with differentiationmicrovessel density or TNM staging [108]
Upregulation of FasL and downregulation of Fas havebeen shown to occur in oral carcinogenesis possibly con-tributing to both cancer cell survival and evasion of the hostimmune assault through induction of apoptosis in T cellsthat would normally kill tumor cells [109] Moreover it hasbeen found that Fas is expressed in low quantities in OSCCwhereas FasL expression correlates negatively with degree ofdifferentiation and apoptosis in OSCC [110] Thus variousproteins (apoptotic and antiapoptotic) have got a significantbearing in initiation progression and prognosis of OSCC
37 Apoptosis and Salivary Gland Tumors Salivary glandtumors (SGT) are relatively uncommon neoplasms withwidely variable histopathologic and biologic characteristicsP53bcl-2 immunostaining reactivity could be helpful indemonstrating SGT behavior in terms of progression andextent of invasion since all malignant salivary gland tumorswere positive whereas 70 of pleomorphic adenomas (PA)showed negative expression [111] Similarly Nordkvist et alfound p53 overexpression in 20 of the malignant SGT withthe highest prevalence in PLGA squamous cell carcinomaand CaXPA and the lowest in adenoid cystic carcinomaand acinic cell carcinoma but none of the benign PA [112]Expression of p53 in malignant tumors bore no correlationto local recurrence metastatic disease or survival of thepatients [113] Bcl-2 protein expression was found virtuallyin all benign and malignant SGT suggesting its role in thedevelopment and proliferation of these tumors via inhibitionof apoptosis [114] p53 expression apoptotic index and bcl-2 protein are potential prognostic parameters in salivarygland adenoid cystic carcinoma [115] Frequency of apoptosisis inversely related to bcl-2 but not to Bax expression inSGT [116] Survival probability of patients who demonstrated
positive staining for c-erbB-2 or TUNEL or both was lowerthan those with negative staining [117]
4 Conclusion
Understanding the mechanistic machinery of apoptosis iscrucial because it influences both health and disease beinginitiated by various physiologic and pathologic stimuliMore-over the extensive involvement of apoptosis in the patho-genesis of various oral diseases and meticulous knowledgeabout it prompt it to therapeutic intervention at differentcheckpoints This review is an attempt to provide an updateon the crucial role and importance of apoptosis in various oralpathologies
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] A Lawen ldquoApoptosis an introductionrdquo BioEssays vol 25 no 9pp 888ndash896 2003
[2] J F Kerr A H Wyllie and A R Currie ldquoApoptosis abasic biological phenomenon with wide-ranging implicationsin tissue kineticsrdquo British Journal of Cancer vol 26 no 4 pp239ndash257 1972
[3] A Strasser L OrsquoConnor and V M Dixit ldquoApoptosis signalingrdquoAnnual Review of Biochemistry vol 69 pp 217ndash245 2000
[4] N Singh ldquoApoptosis in health and disease and modulation ofapoptosis for therapy an overviewrdquo Indian Journal of ClinicalBiochemistry vol 22 no 2 pp 6ndash16 2007
[5] T-J Fan L-H Han R-S Cong and J Liang ldquoCaspase familyproteases and apoptosisrdquo Acta Biochimica et Biophysica Sinicavol 37 no 11 pp 719ndash727 2005
[6] P C Ashe and M D Berry ldquoApoptotic signaling cascadesrdquoProgress in Neuro-Psychopharmacology and Biological Psychia-try vol 27 no 2 pp 199ndash214 2003
[7] L L Loro O K Vintermyr and A C Johannessen ldquoApoptosisin normal and diseased oral tissuesrdquoOral Diseases vol 11 no 5pp 274ndash287 2005
[8] H Jafarzadeh M Sanatkhani and N Mohtasham ldquoOral pyo-genic granuloma a reviewrdquo Journal of Oral Science vol 48 no4 pp 167ndash175 2006
[9] T Nakamura ldquoApoptosis and expression of BaxBcl-2 proteinsin pyogenic granuloma a comparative study with granulationtissue and capillary hemangiomardquo Journal of Cutaneous Pathol-ogy vol 27 no 8 pp 400ndash405 2000
[10] K Yuan L-Y C Wing and M T Lin ldquoPathogenetic roles ofangiogenic factors in pyogenic granulomas in pregnancy aremodulated by female sex hormonesrdquo Journal of Periodontologyvol 73 no 7 pp 701ndash708 2002
[11] K Yuan and M T Lin ldquoThe roles of vascular endothelialgrowth factor and angiopoietin-2 in the regression of pregnancypyogenic granulomardquo Oral Diseases vol 10 no 3 pp 179ndash1852004
[12] F R Amaral V F Bernardes A P Duarte et al ldquoQuantitativeexpression analysis of apoptoticantiapoptotic genes and associ-ationwith immunolocalization of BAX andBCL-2 in peripheral
8 Journal of Oral Diseases
and central giant cell lesions of the jawsrdquo Tumor Biology vol 32no 5 pp 997ndash1003 2011
[13] J Pammer W Weninger H Hulla P Mazal and R HorvatldquoExpression of regulatory apoptotic proteins in peripheral giantcell granulomas and lesions containing osteoclast-like giantcellsrdquo Journal of Oral Pathology and Medicine vol 27 no 6 pp267ndash271 1998
[14] C Scully and S Porter ldquoOral mucosal disease recurrentaphthous stomatitisrdquo British Journal of Oral and MaxillofacialSurgery vol 46 no 3 pp 198ndash206 2008
[15] T Honma T Saito and Y Fujioka ldquoPossible role of apoptoticcells of the oral epithelium in the pathogenesis of aphthousulcerationrdquoOral Surgery Oral Medicine and Oral Pathology vol59 no 4 pp 379ndash387 1985
[16] J F N Pinto Rodrigues C T Fujiyama Oshima A P RibeiroPaiotti M Franco S S Miki Ihara and D A RibeiroldquoExpression of apoptosis regulatory proteins p53 bcl-2 andbax in recurrent aphthous ulcerationrdquo Journal of the EuropeanAcademy of Dermatology and Venereology vol 26 no 10 pp1247ndash1251 2012
[17] J Gamonal A Bascones A Acevedo E Blanco and A SilvaldquoApoptosis in chronic adult periodontitis analyzed by in situDNA breaks electron microscopy and immunohistochem-istryrdquo Journal of Periodontology vol 72 no 4 pp 517ndash525 2001
[18] F Jarnbring E Somogyi J Dalton A Gustafsson and BKlinge ldquoQuantitative assessment of apoptotic and prolifera-tive gingival keratinocytes in oral and sulcular epithelium inpatients with gingivitis and periodontitisrdquo Journal of ClinicalPeriodontology vol 29 no 12 pp 1065ndash1071 2002
[19] P Kelk A Johansson R Claesson L Hanstrom and S KalfasldquoCaspase 1 involvement in human monocyte lysis induced byActinobacillus actinomycetemcomitans leukotoxinrdquo Infectionand Immunity vol 71 no 8 pp 4448ndash4455 2003
[20] P G Stathopoulou J C Galicia M R Benakanakere C AGarcia J Potempa and D F Kinane ldquoPorphyromonas gingi-valis induce apoptosis in human gingival epithelial cells througha gingipain-dependent mechanismrdquo BMC Microbiology vol 9article 107 2009
[21] T Murata K YaegakiW Qian et al ldquoHydrogen sulfide inducesapoptosis in epithelial cells derived from human gingivalrdquoJournal of Breath Research vol 2 no 1 Article ID 017007 2008
[22] J C Galicia M R Benakanakere P G Stathopoulou and DF Kinane ldquoNeutrophils rescue gingival epithelial cells frombacterial-induced apoptosisrdquo Journal of Leukocyte Biology vol86 no 1 pp 181ndash186 2009
[23] A Kantarci P Augustin E Firatli et al ldquoApoptosis in gingivalovergrowth tissuesrdquo Journal of Dental Research vol 86 no 9pp 888ndash892 2007
[24] VAMurrah andE PGilchrist ldquoAssessment of apoptosis in orallichen planusrdquoOral Surgery OralMedicine Oral Pathology OralRadiology and Endodontics vol 82 no 2 pp 209ndash210 1996
[25] M R Roopashree R V Gondhalekar M C Shashikanth JGeorge S H Thippeswamy and A Shukla ldquoPathogenesis oforal lichen planus a reviewrdquo Journal of Oral Pathology andMedicine vol 39 no 10 pp 729ndash734 2010
[26] R Mattila and S Syrjanen ldquoCaspase cascade pathways inapoptosis of oral lichen planusrdquo Oral Surgery Oral MedicineOral Pathology Oral Radiology and Endodontology vol 110 no5 pp 618ndash623 2010
[27] J M C Brant A C Vasconcelos and L V Rodrigues ldquoRole ofapoptosis in erosive and reticular oral lichen planus exhibiting
[28] B K Bloor F K Malik E W Odell and P R MorganldquoQuantitative assessment of apoptosis in oral lichen planusrdquoOral Surgery OralMedicine Oral Pathology Oral Radiology andEndodontics vol 88 no 2 pp 187ndash195 1999
[29] F A C G D Sousa T C Paradella Y R Carvalho and L EB Rosa ldquoImmunohistochemical expression of PCNA p53 baxand bcl-2 in oral lichen planus and epithelial dysplasiardquo Journalof oral science vol 51 no 1 pp 117ndash121 2009
[30] C Bascones-Ilundain M A Gonzalez-Moles G Esparza-Gomez J A Gil-Montoya and A Bascones-Martınez ldquoImpor-tance of apoptoticmechanisms in inflammatory infiltrate of orallichen planus lesionsrdquo Anticancer Research vol 26 no 1 pp357ndash362 2006
[31] V N Pimentel L S de Matos T C B Soares et al ldquoPerforinand granzyme B involvement in oral lesions of lichen planusand chronic GVHDrdquo Journal of Oral Pathology and Medicinevol 39 no 10 pp 741ndash746 2010
[32] L R Oliveira and S Zucoloto ldquoErythema multiforme minor arevisionrdquoTheAmerican Journal of Infectious Diseases vol 4 no4 pp 224ndash231 2008
[33] E Chrysomali F Lozada-Nur N P Dekker S I Papanicolaouand J A Regezi ldquoApoptosis in oral erythema multiformerdquo OralSurgery Oral Medicine Oral Pathology Oral Radiology andEndodontics vol 83 no 2 pp 272ndash280 1997
[34] R Abe T Shimizu A Shibaki H Nakamura HWatanabe andH Shimizu ldquoToxic epidermal necrolysis and Stevens-Johnsonsyndrome are induced by soluble fas ligandrdquo The AmericanJournal of Pathology vol 162 no 5 pp 1515ndash1520 2003
[35] S Inachi H Mizutani and M Shimizu ldquoEpidermal apop-totic cell death in erythema multiforme and Stevens-Johnsonsyndrome contribution of perforin-positive cell infiltrationrdquoArchives of Dermatology vol 133 no 7 pp 845ndash849 1997
[36] A K Vaishnaw E Toubi S Ohsako et al ldquoThe spectrumof apoptotic defects and clinical manifestations includingsystemic lupus erythematosus in humans with Cd95 (FasApo-1)mutationsrdquoArthritis and Rheumatism vol 42 no 9 pp 1833ndash1842 1999
[37] S White and A Rosen ldquoApoptosis in systemic lupus erythe-matosusrdquo Current Opinion in Rheumatology vol 15 no 5 pp557ndash562 2003
[38] D Shah S Sah and S K Nath ldquoInteraction between glu-tathione and apoptosis in systemic lupus erythematosusrdquoAutoimmunity Reviews vol 12 no 7 pp 741ndash751 2013
[39] S Rajagopalan E C Somers R D Brook et al ldquoEndothelial cellapoptosis in systemic lupus erythematosus a common pathwayfor abnormal vascular function and thrombosis propensityrdquoBlood vol 103 no 10 pp 3677ndash3683 2004
[40] M Bektas P Jolly and D S Rubenstein ldquoApoptotic pathwaysin pemphigusrdquo Dermatology Research and Practice vol 2010Article ID 456841 2010
[41] M Puviani A Marconi E Cozzani and C Pincelli ldquoFas ligandin pemphigus sera induces keratinocyte apoptosis through theactivation of caspase-8rdquo Journal of Investigative Dermatologyvol 120 no 1 pp 164ndash167 2003
[42] B H Roh K U Whang M K Cho Y L Park J S Lee andCW Lee ldquoA study of apoptosis in pemphigus vulgarisrdquo KoreanJournal of Dermatology vol 45 no 7 pp 650ndash658 2007
[43] P Deyhimi and P Tavakoli ldquoStudy of apoptosis in oral pem-phigus vulgaris using immunohistochemical marker Bax and
Journal of Oral Diseases 9
TUNEL techniquerdquo Journal of Oral Pathology andMedicine vol42 no 5 pp 409ndash414 2013
[44] B Pelacho C Natal A Espana I Sanchez-Carpintero MJ Iraburu and M J Lopez-Zabalza ldquoPemphigus vulgarisautoantibodies induce apoptosis inHaCaT keratinocytesrdquo FEBSLetters vol 566 no 1ndash3 pp 6ndash10 2004
[45] K Yoneda T Furukawa Y-J Zheng et al ldquoAn autocrineparacrine loop linking keratin 14 aggregates to tumor necrosisdactor 120572-mediated cytotoxicity in a keratinocyte model ofepidermolysis bullosa simplexrdquo Journal of Biological Chemistryvol 279 no 8 pp 7296ndash7303 2004
[46] P P Sedghizadeh C M Allen K E Anderson D H Kim JR Kalmar and J C Lang ldquoOral graft-versus-host disease andprogrammed cell death pathogenetic and clinical correlatesrdquoOral Surgery OralMedicine Oral Pathology Oral Radiology andEndodontics vol 97 no 4 pp 491ndash498 2004
[47] T A Graubert J H Russell and T J Ley ldquoThe role of granzymeB in murine models of acute graft-versus-host disease and graftrejectionrdquo Blood vol 87 no 4 pp 1232ndash1237 1996
[48] N Zavazava and D Kabelitz ldquoAlloreactivity and apoptosisin graft rejection and transplantation tolerancerdquo Journal ofLeukocyte Biology vol 68 no 2 pp 167ndash174 2000
[49] A Sarin E KHaddad and PAHenkart ldquoCaspase dependenceof target cell damage induced by cytotoxic lymphocytesrdquo Jour-nal of Immunology vol 161 no 6 pp 2810ndash2816 1998
[50] M Enari H Hug and S Nagata ldquoInvolvement of an ICE-likeprotease in Fas-mediated apoptosisrdquo Nature vol 375 no 6526pp 78ndash81 1995
[51] T H Holmstrom and J E Eriksson ldquoPhophorylation basedsignaling in Fas receptor mediated apoptosisrdquo Critical Reviewsin Immunology vol 20 pp 121ndash152 2000
[52] Y H Yoo A C Gilliam D Whitaker-Menezes R Korngoldand G F Murphy ldquoExperimental induction and ultrastructuralcharacterization of apoptosis in marine acute cutaneous graft-versus-host diseaserdquo Archives of Dermatological Research vol289 no 7 pp 389ndash398 1997
[53] Y Hayashi K Yayagi and N Haneji ldquoInvolvement of apoptoticprotease cascade for tissue destruction in Sjogrenrsquos syndromerdquoArchivum Immunologiae et Therapiae Experimentalis vol 48no 5 pp 399ndash403 2000
[54] A I Bolstad and R Jonsson ldquoThe role of apoptosis in Sjogrenrsquossyndromerdquo Annals of Internal Medicine vol 149 no 1 pp 25ndash29 1998
[55] P Manganelli and P Fietta ldquoApoptosis and Sjogren syndromerdquoSeminars in Arthritis and Rheumatism vol 33 no 1 pp 49ndash652003
[56] M Ohlsson K Skarstein A I Bolstad A C Johannessen andR Jonsson ldquoFas-induced apoptosis is a rare event in Sjogrenrsquossyndromerdquo Laboratory Investigation vol 81 no 1 pp 95ndash1052001
[57] M Sisto S Lisi D Lofrumento M DrsquoAmore P Scagliusiand VMitolo ldquoAutoantibodies from Sjogrenrsquos syndrome triggerapoptosis in salivary gland cell linerdquo Annals of the New YorkAcademy of Sciences vol 1108 pp 418ndash425 2007
[58] L S Young C W Dawson and A G Eliopoulos ldquoViruses andapoptosisrdquo British Medical Bulletin vol 53 no 3 pp 509ndash5211997
[59] B M Polster J Pevsner and J M Hardwick ldquoViral Bcl-2homologs and their role in virus replication and associateddiseasesrdquo Biochimica et Biophysica Acta vol 1644 no 2-3 pp211ndash227 2004
[60] S Cooray ldquoThe pivotal role of phosphatidylinositol 3-kinase-Akt signal transduction in virus survivalrdquo Journal of GeneralVirology vol 85 no 5 pp 1065ndash1076 2004
[61] J G Teodoro andP E Branton ldquoRegulation of apoptosis by viralgene productsrdquo Journal of Virology vol 71 no 3 pp 1739ndash17461997
[62] M L Nguyen and J A Blaho ldquoApoptosis during herpes simplexvirus infectionrdquo Advances in Virus Research vol 69 pp 67ndash972006
[63] A Kather M J Raftery G Devi-Rao et al ldquoHerpes simplexvirus type 1 (HSV-1)-induced apoptosis in human dendriticcells as a result of downregulation of cellular FLICE-inhibitoryprotein and reduced expression of HSV-1 antiapoptotic latency-associated transcript sequencesrdquo Journal of Virology vol 84 no2 pp 1034ndash1046 2010
[64] L Aurelian ldquoHSV-induced apoptosis in herpes encephalitisrdquoCurrent Topics in Microbiology and Immunology vol 289 pp79ndash111 2005
[65] J Ennaciri J Menezes F Proulx and B J Toledano ldquoInductionof apoptosis by herpes simplex virus-1 in neonatal but not adultneutrophilsrdquo Pediatric Research vol 59 no 1 pp 7ndash12 2006
[66] A M Fuentes-Gonzalez A Contreras-Paredes J Manzo-Merino and M Lizano ldquoThe modulation of apoptosis byoncogenic virusesrdquo Virology Journal vol 10 article 182 2013
[67] MThomas and L Banks ldquoInhibition of Bak-induced apoptosisby HPV-18 E6rdquo Oncogene vol 17 no 23 pp 2943ndash2954 1998
[68] M Roshal Y Zhu and V Planelles ldquoApoptosis in AIDSrdquoApoptosis vol 6 no 1-2 pp 103ndash116 2001
[69] N W Cummins and A D Badley ldquoMechanisms of HIV-associated lymphocyte apoptosis 2010rdquo Cell Death and Diseasevol 1 no 11 article e99 2010
[70] A M Loyola S V Cardoso G S Lisa et al ldquoApoptosis inepithelial cells of apical radicular cystsrdquo International Endodon-tic Journal vol 38 no 7 pp 465ndash469 2005
[71] T Suzuki H Kumamoto K Kunimori andKOoya ldquoImmuno-histochemical analysis of apoptosis-related factors in liningepithelium of radicular cystsrdquo Journal of Oral Pathology andMedicine vol 34 no 1 pp 46ndash52 2005
[72] C A Martins E R C Rivero R M Dufloth C P Figueiredoand D S C Vieira ldquoImmunohistochemical detection of factorsrelated to cellular proliferation and apoptosis in radicular anddentigerous cystsrdquo Journal of Endodontics vol 37 no 1 pp 36ndash39 2011
[73] E Kichi Y Enokiya T Muramatsu et al ldquoCell proliferationapoptosis and apoptosis-related factors in odontogenic kerato-cysts and in dentigerous cystsrdquo Journal of Oral Pathology andMedicine vol 34 no 5 pp 280ndash286 2005
[74] A Piattelli M Fioroni and C Rubini ldquoDifferentiation ofodontogenic keratocysts from other odontogenic cysts by theexpression of bcl-2 immunoreactivityrdquo Oral Oncology vol 34no 5 pp 404ndash407 1998
[75] G C P Mateus G H D S P Lanza P H R deMoura H A deMarigo and M C R Horta ldquoCell proliferation and apoptosisin keratocystic odontogenic tumorsrdquo Medicina Oral PatologiaOral y Cirugia Bucal vol 13 no 11 pp E697ndashE702 2008
[76] L Artese A Piattelli C Rubini et al ldquop16 expression inodontogenic tumorsrdquo Tumori vol 94 no 5 pp 718ndash723 2008
[77] L Lo Muzio S Staibano G Pannone et al ldquoExpression of cellcycle and apoptosis-related proteins in sporadic odontogenickeratocysts and odontogenic keratocysts associated with thenevoid basal cell carcinoma syndromerdquo Journal of DentalResearch vol 78 no 7 pp 1345ndash1353 1999
10 Journal of Oral Diseases
[78] D K Kim S G Ahn J Kim and J H Yoon ldquoComparativeKi-67 expression and apoptosis in the odontogenic keratocystassociated with or without an impacted tooth in addition tounilocular and multilocular varietiesrdquo Yonsei Medical Journalvol 44 no 5 pp 841ndash846 2003
[79] M Andric B Dozic B Popovic et al ldquoSurvivin expression inodontogenic keratocysts and correlation with cytomegalovirusinfectionrdquo Oral Diseases vol 16 no 2 pp 156ndash159 2010
[80] I R H Kramer J J Pindborg and M ShearWHOHistologicalTyping of Odontogenic Tumours Springer Berlin Germany1992
[81] H Kumamoto and K Ooya ldquoDetection of mitochondria-mediated apoptosis signaling molecules in ameloblastomasrdquoJournal of Oral Pathology and Medicine vol 34 no 9 pp 565ndash572 2005
[82] H Kumamoto and K Ooya ldquoImmunohistochemical detectionof BH3-only proteins in ameloblastic tumorsrdquo Oral Diseasesvol 14 no 6 pp 550ndash555 2008
[83] H Kumamoto and K Ooya ldquoExpression of tumor necrosisfactor120572 TNF-related apoptosis-inducing ligand and their asso-ciated molecules in ameloblastomasrdquo Journal of Oral Pathologyand Medicine vol 34 no 5 pp 287ndash294 2005
[84] H Kumamoto K Kimi and K Ooya ldquoImmunohistochemicalanalysis of apoptosis-related factors (Fas Fas ligand caspase-3and single-stranded DNA) in ameloblastomasrdquo Journal of OralPathology and Medicine vol 30 no 10 pp 596ndash602 2001
[85] T E Carneiro S A Marinho F D Verli A T M Mesquita NL Lima and J L Miranda ldquoOral squamous papilloma clinicalhistologic and immunohistochemical analysesrdquo Journal of oralscience vol 51 no 3 pp 367ndash372 2009
[86] T Yamaguchi M Shindoh A Amemiya et al ldquoDetectionof human papillomavirus type 2 related sequence in oralpapillomardquo Analytical Cellular Pathology vol 16 no 3 pp 125ndash130 1998
[87] J H Main and M Pavone ldquoActinic cheilitis and carcinoma ofthe liprdquo Journal of Canadian Dental Association vol 60 no 2pp 113ndash116 1994
[88] A Martınez U Brethauer I G Rojas et al ldquoExpression ofapoptotic and cell proliferation regulatory proteins in actiniccheilitisrdquo Journal of Oral Pathology and Medicine vol 34 no5 pp 257ndash262 2005
[89] M A Birchall C MWinterford D J Allan and B V HarmonldquoApoptosis in normal epithelium premalignant and malignantlesions of the oropharynx and oral cavity a preliminary studyrdquoEuropean Journal of Cancer B vol 31 no 6 pp 380ndash383 1995
[90] N Tanda S Mori K Saito K Ikawa and S SakamotoldquoExpression of apoptotic signaling proteins in leukoplakia andoral lichen planus quantitative and topographical studiesrdquoJournal of Oral Pathology and Medicine vol 29 no 8 pp 385ndash393 2000
[91] G Kovesi and B Szende ldquoProgression of the leukoplakia isassociated to changes in apoptotic and mitotic index as well asin p53 and Ki-67 expressionrdquo Oncology vol 46 no 4 pp 333ndash338 2002
[92] H Tsuzuki S Fujieda H Sunaga N Narita M Tokuriki andH Saito ldquoExpression of p27 and apoptosis in oral leukoplakiardquoAnticancer Research vol 23 no 2 pp 1265ndash1270 2003
[93] E Chrysomali J S Greenspan N Dekker D Greenspanand J A Regezi ldquoApoptosis-associated proteins in oral hairyleukoplakiardquo Oral Diseases vol 2 no 4 pp 279ndash284 1996
[94] S H Kaufmann andG J Gores ldquoApoptosis in cancer cause andcurerdquo BioEssays vol 22 pp 1007ndash1017 2000
[95] S Ghavami M Hashemi S R Ande et al ldquoApoptosis andcancer mutations within caspase genesrdquo Journal of MedicalGenetics vol 46 no 8 pp 497ndash510 2009
[96] C M Coutinho-Camillo S V Lourenco I N NishimotoL P Kowalski and F A Soares ldquoCaspase expression in oralsquamous cell carcinomardquo Head and Neck vol 33 no 8 pp1191ndash1198 2011
[97] P J Polverini and J E Nor ldquoApoptosis and predisposition tooral cancerrdquo Critical Reviews in Oral Biology and Medicine vol10 no 2 pp 139ndash152 1999
[98] M Sulkowska W Famulski S Sulkowski et al ldquoCorrelationbetween Bcl-2 protein expression and some clinicopathologicalfeatures of oral squamous cell carcinomardquo Polish Journal ofPathology vol 54 no 1 pp 49ndash52 2003
[99] L L Loro O K Vintermyr P G Liavaag R Jonsson and A CJohannessen ldquoOral squamous cell carcinoma is associated withdecreased bcl-2bax expression ratio and increased apoptosisrdquoHuman Pathology vol 30 no 9 pp 1097ndash1105 1999
[100] M Baltaziak M KodaM Barwijuk-Machała et al ldquoThe role ofBak expression in apoptosis of the oral squamous cell carcinoma(OSCC) and metastases to lymph nodes (LNMs)rdquo AnnalesAcademiae Medicae Bialostocensis vol 49 pp 14ndash15 2004
[101] J C de Vicente L M J Gutierrez A H Zapatero M FF Forcelledo G Hernandez-Vallejo and J S Lopez ArranzldquoPrognostic significance of p53 expression in oral squamous cellcarcinoma without neck node metastasesrdquo Head and Neck vol26 no 1 pp 22ndash30 2004
[102] M A Gonzalez-Moles P Galindo J Gutierrez-Fernandez etal ldquoP53 protein expression in oral squamous cell carcinomasurvival analysisrdquo Anticancer Research vol 21 no 4 pp 2889ndash2894 2001
[103] S Kannan G Jagadeesh Chandran K Raveendran Pillai et alldquoExpression of p53 in leukoplakia and squamous cell carcinomaof the oral mucosa correlation with expression of Ki67rdquo Journalof Clinical Pathology vol 49 no 3 pp M170ndashM175 1996
[104] J Y Koh N P Cho G Kong J D Lee and K Yoon ldquop53mutations and human papillomavirus DNA in oral squamouscell carcinoma correlation with apoptosisrdquo British Journal ofCancer vol 78 no 3 pp 354ndash359 1998
[105] L LoMuzio G Pannone S Staibano et al ldquoSurvivin expressionin oral squamous cell carcinomardquo British Journal of Cancer vol89 no 12 pp 2244ndash2248 2003
[106] Y Jinbu K Tsukinoki N Miyagi et al ldquoExpression of survivinin oral squamous cell carcinomardquo Oral Med Pathol vol 11 pp41ndash44 2006
[107] C Jane A V Nerurkar N V Shirsat R B DeshpandeA D Amrapurkar and F R Karjodkar ldquoIncreased survivinexpression in high-grade oral squamous cell carcinoma a studyin Indian tobacco chewersrdquo Journal of Oral Pathology andMedicine vol 35 no 10 pp 595ndash601 2006
[108] Y-H Kim S-M Kim Y-K Kim S-P Hong M-J Kim andH Myoung ldquoEvaluation of survivin as a prognostic marker inoral squamous cell carcinomardquo Journal of Oral Pathology andMedicine vol 39 no 5 pp 368ndash375 2010
[109] N G Nikitakis J J Sauk and S I Papanicolaou ldquoThe role ofapoptosis in oral disease mechanisms aberrations in neoplas-tic autoimmune infectious hematologic and developmentaldiseases and therapeutic opportunitiesrdquo Oral Surgery OralMedicine Oral Pathology Oral Radiology and Endodontics vol97 no 4 pp 476ndash490 2004
[110] L L Loro O K Vintermyr A C Johannessen P G Liavaagand R Jonsson ldquoSuppression of Fas receptor and negative
Journal of Oral Diseases 11
correlation of Fas ligand with differentiation and apoptosis inoral squamous cell carcinomardquo Journal of Oral Pathology andMedicine vol 28 no 2 pp 82ndash87 1999
[111] N H Al-Rawi H Omer and S Al Kawas ldquoImmunohistochem-ical analysis of P53 and bcl-2 in benign and malignant salivaryglands tumorsrdquo Journal of Oral Pathology and Medicine vol 39no 1 pp 48ndash55 2010
[112] ANordkvist E Roijer G Bang et al ldquoExpression andmutationpatterns of p53 in benign andmalignant salivary gland tumorsrdquoInternational Journal of Oncology vol 16 no 3 pp 477ndash4832000
[113] V J Karja K J Syrjanen A-K Kurvinen and S M SyrjanenldquoExpression and mutations of p53 in salivary gland tumoursrdquoJournal of Oral Pathology and Medicine vol 26 no 5 pp 217ndash223 1997
[114] M Yanezez I Roa M Garcıa G Ibacache and M VillasecaldquoGene Bcl-2 protein expression in salivary gland tumorsrdquoRevista Medica de Chile vol 127 no 2 pp 139ndash142 1999
[115] L Jia R L Esguerra X Tang et al ldquoPrognostic value ofapoptosis and apoptosis-associated proteins in salivary glandadenoid cystic carcinomardquo Pathology International vol 54 no4 pp 217ndash223 2004
[116] Y Soini U Tormanen and P Paakko ldquoApoptosis is inverselyrelated to bcl-2 but not to bax expression in salivary glandtumoursrdquo Histopathology vol 32 no 1 pp 28ndash34 1998
[117] R M Nagler H Kerner S Ben-Eliezer I Minkov and O Ben-Itzhak ldquoPrognostic role of apoptotic Bcl-2 c-erbB-2 and p53tumor markers in salivary gland malignanciesrdquo Oncology vol64 no 4 pp 389ndash398 2003
322 Apoptosis and Diseases of Periodontium Periodontaldisease is an acute or chronic inflammatory condition whichdevelops as a result of imbalance in the equilibrium betweenthe host defence andmicrobial agents resulting in destructionof tooth-supporting tissue leading to mobility and tooth lossTUNEL positive cells positive staining with active caspase-3 Fas FasL p53 and chromatin condensation was found inthe inflammatory infiltrates of periodontitis patients whereasBcl-2 positivity was found in both periodontitis patients andhealthy controls thus concluding that apoptotic mechanismcould be implicated in the inflammatory process associatedwith periodontitis [17] A greater number of apoptotic ker-atinocytes than proliferative ones are found in periodon-titis patients only in the most apical part of the sulcuscompared to those with gingivitis [18] Monocytes are themost lysis-sensitive leukocytes for A actinomycetemcomitansleukotoxin which depends on caspase 1-activation [19] It isalso evidenced that live P gingivalis can induce significantapoptosis in primary human gingival epithelial cells between12 and 24 hours of challenge via gingipains dependentmechanism [20] Hydrogen sulfide can induce apoptosis ingingival epithelial cells and human gingival fibroblast inthe oral cavity which may cause a periodontal condition[21] Neutrophils when combined in a P gingivalis challengeassay of epithelial cells prevent epithelial cell apoptosis byphagocytosing P gingivalis and also protect the host fromthe harmful effects of its microbial proteases [22] It has alsobeen analysed that the increased fibroblast proliferation anda simultaneous decrease in apoptosis contribute to gingivalovergrowth [23]
33 Apoptosis and Immune-Mediated Diseases
331 Apoptosis and Oral Lichen Planus The hallmarkhistopathologic feature of lichen planus (LP) is the degen-eration of the basal layer of the epithelium Eosinophilicglobular bodies also known as colloid hyaline cytoid orCivatte bodies are also characteristic features of LP seen inthe basal layer and upper connective tissue and have beeninterpreted as degenerative keratinocytes Damage to thebasal layer appears to involve apoptosis as an early event [24]The following mechanisms are proposed for keratinocyteapoptosis
(1) T-cell-secreted TNF-120572 binding to TNF-120572 R1 receptoron keratinocyte surface
(2) T-cell surface CD95L (Fas ligand) binding to CD95(Fas) on the keratinocyte surface
(3) T-cell-secreted granzyme B entering the keratinocytevia perforin induced membrane pores
All these mechanisms activate caspase cascade resultingin keratinocyte apoptosis On the contrary reduced or absentapoptotic rate in inflammatory cells has been thought tocontribute to development of OLP [25]
One of the studies demonstrated that caspases 2 and 12were expressed in all samples and caspase-8 was expressed inmost of the samples of atrophic lichen planus suggesting theimportance of endoplasmic reticulum (ER) stress in inducing
apoptosis in OLPs However the activation of death receptorsin OLP cannot be ruled out [26] Increased apoptosis maycause a decrease in epithelial thickness reflected in the activityof the lesion It was found that apoptosis in the erosiveOLP was significantly more intense than in the reticulartype and both forms of OLP presented more apoptosis thanthe healthy oral mucosa [27] It has been demonstratedthat increased numbers of apoptosis were detected in OLPespecially in association with lymphocytic infiltration andhematoxylin-eosin staining being more sensitive in detectinghigher number of apoptotic nuclei than in situ end labeling[28] Expression of cell proliferation proteins like PCNAand apoptotic proteins like Bcl-2 and Bax was found to bealtered in OLP as seen in epithelial dysplasia suggestingtheir potential for malignant transformation [29] TUNELand caspase-3 expression showed absence or low rate ofapoptosis in inflammatory cells in OLP thus contributingto the persistence of the inflammation and favouring cancerdevelopment [30] Apoptosis in OLP seems to be correlatedwith granzyme B release while in oral cGVHD perforinseems to bemore important suggesting that subtle differencesseem to exist in their pathogenetic mechanisms [31]
332 Apoptosis and Erythema Multiforme Erythema multi-forme is a distinct dermatologic hypersensitivity pathologycharacterized by cutaneous or mucous lesions and eventuallyit can also involve both In their more severe forms theyappear with occasional visceral involvements It includeswide range of clinical patternsmdashEM minor EM majorStevens Johnson syndrome and toxic epidermal necrolysis[32] Cell death in EM is at least in part due to apoptosiswhich may be related to an altered expression of apoptosis-regulating proteins like p53 and Bcl-2 family proteins andactivation of FasFas-ligand system [33] ELISA and in vitroanalysis showed that sFasL secreted by PBMCs not ker-atinocytes plays a crucial role in the keratinocyte apoptosisand pathogenetic mechanism of TEN and SJS and serumsFasL level may be a good indicator for the early diagnosisof TEN and SJS [34] It has also been found that perforinmediates apoptosis in the pathogenesis of the epidermal cellchanges in SJS [35]
333 Apoptosis and Lupus Erythematosus Systemic lupuserythematosus (SLE) and discoid lupus erythematosus (DLE)are autoimmune diseases manifesting as erythematous orulcerative lesions with white striae radiating from the mar-gins [7] CD95 mutations are linked with loss of regulation ofB lymphocytes which predisposes to systemic autoimmunityincluding SLE [36] Autoantigens in SLE become clustered inand on the surface blebs of apoptotic cells and these cells playa central role in tolerizing B cells andT cells andmay drive theautoimmune response in systemic autoimmune disease [37]SLE is characterized by imbalance redox state which in turnis related to intracellular levels of glutathione and controlledproduction of reactive oxygen species and alteration in theintracellular redox environment of cells are critical for cellularimmune dysfunction activation of apoptotic enzymes andapoptosis [38] It has also been demonstrated that elevatedendothelial cell apoptosis strongly correlates with markedly
4 Journal of Oral Diseases
abnormal vascular function and elevated tissue factor levelsandmay represent an importantmechanism for developmentof atherothrombosis in SLE [39]
334 Apoptosis and Pemphigus Vulgaris Pemphigus is agroup of autoimmune blistering diseases characterized byloss of keratinocyte cell adhesion that leads to clinical blisterformation Induction of apoptosis or of proapoptotic proteinsby pemphigus IgGmay be (i) part of themechanism bywhichsera and IgG induce acantholysis or (ii) a consequence of lossof adhesion (anoikis) and a result of acantholysis [40] Fasligand levels are markedly increased in sera from untreatedpemphigus patients which is suggesting that FasFas lig-and cell death pathway plays amajor role in anoikis as seen inpemphigus [41] Hoechst 33342 staining andRT-PCR analysisshowed that apoptosis may be associated with acantholysisof pemphigus lesional epidermis and may play an importantrole in the pathogenesis of pemphigus [42] Apoptosis isobserved in the perilesional normal appearing tissue sug-gesting that it is an early phenomenon Also the process ofapoptosis may cause exacerbation or speeding of the bullaformation [43] But whether apoptosis is really essential foracantholysis in pemphigus is not clear Immunofluorescenceanalysis confirmed that PV IgG autoantibodies promoteapoptosis in HaCaT keratinocytes characterized by caspase-3activation Bcl-2 depletion and Bax expression [44]
335 Apoptosis and Epidermolysis Bullosa Epidermolysisbullosa is a hereditary vesiculobullous disease characterizedby blistering of the skin and oral mucosa due to basalkeratinocyte fragility [7] Experiment using cellular model ofEBS showed thatHaCaT cells were susceptible to apoptosis byactivation of caspases 3 and 8 but not caspase-9 or caspase-12 Moreover TNF-120572 release and the subsequent activationof the TNF-120572 receptor by an autocrineparacrine pathwaylink protein aggregates to cell death in this keratinocyteEBS cellular model Also susceptibility of keratinocytes tocaspase-8-mediated apoptosis is increased in mutated K14because of impairment of the cytoprotective mechanismmediated by K14-TRADD interaction [45]
336 Apoptosis and Oral Graft-versus-Host Diseases Graft-versus-host disease (GVHD) is characterized by an immune-mediated attack by donor immune cells against variousrecipient host cells and tissues Although donor and recip-ient are matched at major histocompatibility loci prior totransplantation GVHD occurs because differences exist atminor histocompatibility loci Programmed cell death orapoptosis has been evidenced as major constituent in thepathogenesis of GVHD Oral involvementmay be seen in 33ndash75 of patients who develop acute GVHD and in up to 80of patients affected by chronic GVHD making these lesionsuseful as a highly predictive index for the presence of systemicdisease The oral lesions of GVHD are clinically and histo-logically lichenoid in nature [46] CTL mediated apoptoticpathway predominates in GVHD Initiation can occur eitherwhen virus-specific cytotoxic T lymphocytes (CTL) bind totarget cells and release granzymes into the cells or when CTL
bind and activate the TNF family of receptors such as the Fas-receptor or TRAIL-receptor [46ndash48] Caspases and severalintracellular proteases participate in propagating and actuat-ing the apoptotic death signal through a proteolytic cleavagecascade [49 50] Phosphorylation pathways regulate signaltransduction cascades [51] However experimental murinemodels of acute GVHD demonstrated that apoptosis can beinduced even in the absence of immune cells suggestingexistence of an additional mechanism for target cell injury[52]
337 Apoptosis and Sjogrenrsquos Syndrome Sjogrenrsquos syndrome(SS) is an autoimmune disease characterized by diffuselymphoid cell infiltrates in the salivary and lacrimal glandsresulting in symptoms of dry mouth and eyes [53] Threeaspects of apoptosis are related to SS (i) defective apopto-sis could lead to lymphoid cell accumulation and chronicinflammation in exocrine glands (ii) increased apoptosis ofepithelial cells might explain the loss of secreting epitheliumand (iii) orderly destruction of cellular components mightinduce autoantibody production [54] Apoptosis of the acinarand ductal epithelial cells of the salivary and lacrimal glandsmay be induced by either CTL through the release perforinand granzyme B or the interaction of Fas ligand expressedby T lymphocytes with Fas on epithelial cells [55] On thecontrary others believed that Fas-induced apoptosis amongSS salivary glands is a rare event despite their abundantexpression since infiltratingmononuclear cells seem to escapeapoptosis resulting in foci of inflammatory cells [56] 120 kDa120572-Fodrin is an important autoantigen in the developmentof SS in animal models and SS patients Anti-Fas antibody-induced apoptosis and an increase in the activities of calpainand caspases may be involved in the progression of 120572-fodrin proteolysis and tissue destruction in the developmentof SS [53] In vitro analysis demonstrated that apoptosistriggered by anti-Ro and anti-La could be responsible for theimpairment of the secretory function in the salivary glands[57]
34 Apoptosis and Virus Associated Diseases Various typesof viruses have been involved in the pathogenesis of dif-ferent oral lesions the commonest being herpes simplexvirus (HSV) human papillomaviruses (HPV) and humanimmunodeficiency virus (HIV) Virus infected cells can oftenbe recognized and destroyed by apoptotic processes initiatedby either CTL or certain cytokines Many viruses directlyinduce apoptosis during infection which is at least partiallyresponsible for the various viral pathologies Many viruseshave evolved with multiple distinct mechanisms to blockthe premature apoptosis of infected cells either facilitatingthe maintenance of persistent infection or prolonging thesurvival of lytically infected cells such that the production ofprogeny virus is maximized [58] Examples include blockageof apoptosis by viral BCL-2 (vBCL-2) homologues [59] uti-lization of the phosphatidylinositol 3-kinase-Akt signallingpathway [60] or suppression of inducers of apoptosis suchas p53 [61]
HSV infection triggers apoptosis in infected cells How-ever proteins synthesized later in infected cells prevent
Journal of Oral Diseases 5
apoptotic cell death from ensuingThis apoptoticmodulationhas a role in the development of herpetic disease [62] HSV-1-induced apoptosis of immature dendritic cells is associatedwith downregulation of the cellular FLICE-inhibitory protein(c-FLIP) in a proteasome-independent manner [63] HSV-1triggers apoptosis in CNS neurons and causes encephalitis inadult subjects [64] HSV-1 enhances apoptosis via expressionof both Fas and Fas ligand on the surface of neonatalneutrophils [65]
High risk HPV oncoproteins E6 E7 and E5 can mod-ulate host mediated apoptosis by inhibiting death receptorsignaling and thus regulate the survival of infected cells [66]HPV E6 proteins inhibit apoptosis in both p53-dependentand p53-independent manners HPV-18 E6 inhibits Bak-induced apoptosis in differentiating keratinocytes in whichHPV replicates It was also suggested that Bak is probably thefirst naturally occurring target of ubiquitin ligase E6AP [67]
HIV infection usually leads to progressive immunod-eficiency and loss of immune competence associated withdeclines in both the functionality and the number of CD4+lymphocytes which in turn is related to various viral andimmunological processes Proposed virus-mediated mech-anisms include toxicity caused by accumulation of uninte-grated viral DNA alteration in membrane permeability dueto budding of viral particles and terminal differentiationAmong the immunological mechanisms are killing by spe-cific CTL and signaling through the CD4 molecule leadingto CD4+ lymphocytes apoptosis [68] Apoptosis in HIV maybe stimulated by environmental stress toxins and removalof growth factors and may be mediated by one of thesedeath inducing ligands TNF FasL and TRAIL [69] Manyof the proteins that are encoded by the HIV genome havebeen found to have pro- andor antiapoptotic qualities HIVsurface glycoprotein gp120 cross-links CD4 and primes cellsfor apoptosis HIV-1 can also induce apoptosis ldquofrom withinrdquovia expression of certain viral genes such as tat nef vpu andvpr [68 69]
35 Apoptosis and Benign Entities
351 Apoptosis and Benign Odontogenic Cysts and Tumors
(1) Apoptosis and RadicularApical Cyst Radicular cysts arethe most common cystic lesions of the jaws and representa periapical inflammatory disease evoked by infected andnecrotic dental pulp Apoptosis was found to be alwayspresent in the epithelium of the apical radicular cyst Higherapoptotic index (AI) and bcl-2 index (bcl-2I) were found inlesions with atrophic compared to hyperplastic epitheliumbut the difference was statistically insignificant However apositive and significant correlation was found between AIand bcl-2I [70] Epithelium of radicular and residual cystsshowed expression of apoptosis related factors like ssDNAp53 Bax Bcl-2 caspase-3 Fas Fas-L and Ki-67 antigensuggesting their role in the pathophysiologic activity ofperiapical inflammatory lesions Such factors may be affectedby the structure of lining epithelium and the degree ofinflammatory change since Ki-67 and ssDNA reactivity inRCs with intense inflammatory reactions or with thick lining
epithelium were significantly stronger than those RCs withless inflammation or with thin lining [71] Caspase-3 andKi-67 expression was significant in hyperplastic epitheliumrelated to intense inflammation whereas Bcl-2 expressionwas significantly higher in atrophic epithelium of DCs thanRCs suggesting that although they may have different patho-genetic mechanism they have similar biological behavior inthe presence of intense inflammatory infiltrate [72]
(2) Apoptosis and Dentigerous Cyst The epithelial lining ofDCs has shown TUNEL Ki-67 and p53 positivity but theexpression was weak as compared to OKCs indicating thatapoptosis is involved in cyst formation and maintainingthe regular thickness of the lining epithelium in DCs [73]Bcl-2 positivity was significantly higher in atrophic epithe-lium of DCs than that of RCs suggesting that presence ofinflammation inhibits the Bcl-2 expression and both cystshave similar biological behavior in the presence of intenseinflammatory infiltrate [72] whereas other demonstrated thatBcl-2 expression was almost completely negative in DCs andRCs compared to OKCs [74]
(3) Apoptosis and Odontogenic KeratocystKeratocystic Odon-togenic Tumor Keratocystic odontogenic tumor (KCOT)also known as odontogenic keratocyst (OKC) was recentlyclassified as a benign neoplasia due to the aggressive clinicalbehavior The proliferation index and apoptotic index werefound to be higher and with distinct pattern in both sporadicand nevoid basal cell carcinoma syndrome (NBCCS) KCOTscompared to DCs reflecting its high cell turnover andreinforcing its classification as an odontogenic tumor [75]Lack of p16 expression in KCOT compared to strong ormoderate p16 expression in RCs and follicular cysts couldbe related to the increased aggressive behavior invasivenessand high frequency of recurrences found in KCOT [76]Overexpression of cyclin Dl and p53 in syndromic OKCscould be considered as hallmark of a mutated cellular phe-notype and more aggressive clinical behaviour compared tosporadic KCOTs which were negative for these oncoproteins[77] Strong Bcl-2 overexpression in OKCs suggests its rolein extension of cell survival leading to the peculiar aggressivegrowth pattern and can be useful to differentiate OKC fromother odontogenic cysts [74] TUNEL positive cells wereobserved in the surface layers of OKCs whereas no positivitywas seen in the basal or intermediate layers of OKCs andDCs Also Ki67-positive ratio and p53-positive ratio in theintermediate layer were the highest in OKCs and Bcl-2-positive cells were discernible exclusively in the basal layerof OKCs signifying that subsequently OKCs are seen ascystic lesions but not as tumor masses [73] There is nosignificant difference in proliferative activity and apoptosisin OKCs associated with or without impacted teeth orbetween the unilocular ormultilocular variants [78] Survivinimmunoexpression was positive in all cases of OKCs while allperiapical cysts were negative suggesting its contribution toviolent behavior of OKCs [79]
(4) Apoptosis and Ameloblastomas Ameloblastoma isthe most frequently encountered tumor arising from
6 Journal of Oral Diseases
odontogenic epithelium and is characterized by a benign butlocally invasive behavior with a high risk of recurrence [80]
RT-PCR and IHC showed expression of cytochrome cAPAF-1 caspase-9 and AIF in tooth germs and benign andmalignant ameloblastomas suggesting that themitochondria-mediated apoptotic pathway has a role in apoptotic celldeath of normal and neoplastic odontogenic epithelium andmight be involved in oncogenesis cytodifferentiation andmalignant transformation of odontogenic epithelium [81]
Granular cells basal cells desmoplastic ameloblastomasand ameloblastic carcinomas showed immunoreactivity forthe BH3-only proteins (Bid Bim Bad Noxa and Puma)whereas keratinising cells of acanthomatous ameloblastomasshowed no reactivity suggesting that these proteins mightbe involved in tumor cell differentiation of ameloblastomas[82] TNF-120572 TRAIL and their receptors were also found tobe expressed in tooth germs and ameloblastomas provingtheir role in cytodifferentiation of odontogenic epitheliumand tissue structuring of ameloblastomas [83] Similarlyexpression of Fas FasL caspase-3 and ssDNA has also beendemonstrated in various patterns in tooth germs and benignand malignant ameloblastomas [84]
352 Apoptosis and Benign Epithelial Tumor
(1) Apoptosis and Squamous PapillomaOral squamous papil-loma (OSP) is a frequent benign tumorous lesion associatedwith HPV OSP consists of proliferation of the stratifiedsquamous epithelium resulting in a papillary or verrucousexophytic mass and has got site predilection for the tongueand soft palate but any surface of the oral cavity can beaffected [85 86] Carneiro et al performed immunohisto-chemical assay on 12 OSP cases utilizing BP53-12 and Pab240antibodies for p53 protein and found that immunostainingfor protein p53 was primarily negative or weakly positivein all cases (in all epithelial layers) except one case whichindicates the benign nature of the lesions evidenced by theirslow development and less chances of becoming malignantIntense staining in one slide for both immunomarkers in allthe epithelial layers could be attributed to the presence ofvirus with high oncogenic potential (HPV 16 and 18) or tothe presence of coexisting external factors [85]
36 Apoptosis and Premalignant and Malignant Entities
361 Apoptosis and Actinic Cheilitis Actinic cheilitis (AC) isa common condition caused by damage to the lips throughexposure to sunlight and has the potential to undergomalignant transformation into squamous cell carcinoma [87]Overexpression of p53 was found in AC as compared tonormal lip and oral mucosa Bcl-2 expression was higherin AC than in oral mucosa but it was significantly reducedas compared with normal lip Thus it was suggested thatDNA-damaged cells by UV radiation in AC are eliminatedby apoptosis Also both p53 and bcl-2 play an important rolein regulating malignant transformation in AC [88]
362 Apoptosis and Oral Leukoplakia It has been sug-gested that a change in apoptosis accompanies the onset
of invasion in a premalignant lesion of the human oralcavity and oropharynx AI increased progressively fromnormal to carcinoma in situ (CIS) but fell in SCC withmaximum apoptotic index (AI) mitotic index (MI) ratioin CIS The position of apoptotic bodies was localised tothe deepest layers in normal and dysplastic epithelia butbecame generalised in CIS and SCC [89] Greater expressionof oncoproteins MDM2 and Bcl-2 was seen in leukoplakiawith altered keratinocyte maturation than OLP case whereasexpression of wt-p53 and p21 was higher in OLP compared toleukoplakia cases In spite of divergent outcome of apoptoticsignalling proteins no significant difference in the number ofapoptotic epithelial cells was observed between leukoplakiaand OLP cases [90] Increased mitotic apoptotic and Ki-67 index indicate unfavourable prognosis of leukoplakia [91]Abundance of p27 expression in oral leukoplakia may beassociated with inhibition of cell proliferation leading toapoptosis of premalignant tumor cells thus preventing tumorprogression [92] It is hypothesised that the antiapoptoticability of Epstein-Barr virus (EBV) may result in alteredexpression of apoptosis-associated proteins in oral hairyleukoplakia Except p53 which appears to be overexpressedthere is only slight alteration in immunoexpression of otherapoptosis-associated proteins in OHL [93]
363 Apoptosis and Oral Squamous Cell Carcinoma Theaccumulation of neoplastic cells can occur through enhancedproliferation diminished cell turnover or a combination ofboth processes Tumor cells from a wide variety of humancancers have been shown to exhibit increased survival andresistance to apoptosis [94] There are two major ways thatcould downregulate cancer cell apoptosis (1) somatic andnonsomatic mutation and loss of expression of proapoptoticmolecules and (2) overexpression of apoptosis inhibitorymolecules Mutations within caspase family proteases are notuncommon in malignancies [95] Caspase-7 proved to bean independent prognosticator and predictor of locoregionalrecurrence in patients of OSCC [96] Several alterations thatinhibit both the death receptor and mitochondrial pathwaysvia caspases have also been identified including overexpres-sion of IAPs activation of PI3k or Akt and posttranslationalmodifications of caspases [94]
In pathological settings Bcl-2 gene family appears toact synergistically with oncogenes and tumor suppressorgenes [97] Positive Bcl-2 expression is associated with highertumor grading higher tumor mitotic index higher index ofatypical mitoses and microfocal pattern of tumor invasivemargins [98] In OSCC compared with oral epitheliumthere is a decreased Bcl-2 expression a lowered Bcl-2Baxratio and increased apoptosis Expression of Bax correlatedwith histological tumor grading in OSCC [99] whereasothers found that expression of Bak may be useful for bettercharacterizing and predicting the prognosis of OSCC [100]
Aberrations of the p53 gene and overexpression of its pro-tein are widely recognized markers of malignancy includingOSCC It was found that there is a negative correlation of p53immunoexpression with histologic grade of differentiationIn patients without neck node metastases p53 showed astrong correlation with survival [101] On the contrary
Journal of Oral Diseases 7
another study showed that expression of p53 protein did notbehave as amarker of prognostic value in patients withOSCC[102]
As cancer is characterized by uncontrolled cell prolif-eration markers of proliferation such as Ki67 and PCNAhave been studied extensively in neoplastic lesions Expres-sion of both p53 and Ki67 correlated significantly with thehistopathological stage of the tumor However expression ofp53 was not correlated with that of Ki67 [103]
HPV infection andor p53 mutations are implicated incarcinogenesis of oral SCC but are not mutually exclusiveevents Moreover decrease in apoptosis is more closelyrelated to p53 mutation than HPV infection [104]
Survivin has got a versatile role in modulating celldivision and apoptosis in cancer Low survivin expressioncorrelated statistically significantly with better survival ratesbut not with age sex tumor size the presence of lymphnode or distant metastases [105] Survivin was found tobe preferentially expressed in nonadvanced nonmetastaticand chemotherapy-sensitive OSCC [106] On the contraryincreased expression of survivin was found in high-gradetumors suggesting its contribution to apoptosis resistancein response to therapy [107] Also significant correlationbetween survivin expression lymph node metastasis andproliferation was revealed but not with differentiationmicrovessel density or TNM staging [108]
Upregulation of FasL and downregulation of Fas havebeen shown to occur in oral carcinogenesis possibly con-tributing to both cancer cell survival and evasion of the hostimmune assault through induction of apoptosis in T cellsthat would normally kill tumor cells [109] Moreover it hasbeen found that Fas is expressed in low quantities in OSCCwhereas FasL expression correlates negatively with degree ofdifferentiation and apoptosis in OSCC [110] Thus variousproteins (apoptotic and antiapoptotic) have got a significantbearing in initiation progression and prognosis of OSCC
37 Apoptosis and Salivary Gland Tumors Salivary glandtumors (SGT) are relatively uncommon neoplasms withwidely variable histopathologic and biologic characteristicsP53bcl-2 immunostaining reactivity could be helpful indemonstrating SGT behavior in terms of progression andextent of invasion since all malignant salivary gland tumorswere positive whereas 70 of pleomorphic adenomas (PA)showed negative expression [111] Similarly Nordkvist et alfound p53 overexpression in 20 of the malignant SGT withthe highest prevalence in PLGA squamous cell carcinomaand CaXPA and the lowest in adenoid cystic carcinomaand acinic cell carcinoma but none of the benign PA [112]Expression of p53 in malignant tumors bore no correlationto local recurrence metastatic disease or survival of thepatients [113] Bcl-2 protein expression was found virtuallyin all benign and malignant SGT suggesting its role in thedevelopment and proliferation of these tumors via inhibitionof apoptosis [114] p53 expression apoptotic index and bcl-2 protein are potential prognostic parameters in salivarygland adenoid cystic carcinoma [115] Frequency of apoptosisis inversely related to bcl-2 but not to Bax expression inSGT [116] Survival probability of patients who demonstrated
positive staining for c-erbB-2 or TUNEL or both was lowerthan those with negative staining [117]
4 Conclusion
Understanding the mechanistic machinery of apoptosis iscrucial because it influences both health and disease beinginitiated by various physiologic and pathologic stimuliMore-over the extensive involvement of apoptosis in the patho-genesis of various oral diseases and meticulous knowledgeabout it prompt it to therapeutic intervention at differentcheckpoints This review is an attempt to provide an updateon the crucial role and importance of apoptosis in various oralpathologies
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
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[2] J F Kerr A H Wyllie and A R Currie ldquoApoptosis abasic biological phenomenon with wide-ranging implicationsin tissue kineticsrdquo British Journal of Cancer vol 26 no 4 pp239ndash257 1972
[3] A Strasser L OrsquoConnor and V M Dixit ldquoApoptosis signalingrdquoAnnual Review of Biochemistry vol 69 pp 217ndash245 2000
[4] N Singh ldquoApoptosis in health and disease and modulation ofapoptosis for therapy an overviewrdquo Indian Journal of ClinicalBiochemistry vol 22 no 2 pp 6ndash16 2007
[5] T-J Fan L-H Han R-S Cong and J Liang ldquoCaspase familyproteases and apoptosisrdquo Acta Biochimica et Biophysica Sinicavol 37 no 11 pp 719ndash727 2005
[6] P C Ashe and M D Berry ldquoApoptotic signaling cascadesrdquoProgress in Neuro-Psychopharmacology and Biological Psychia-try vol 27 no 2 pp 199ndash214 2003
[7] L L Loro O K Vintermyr and A C Johannessen ldquoApoptosisin normal and diseased oral tissuesrdquoOral Diseases vol 11 no 5pp 274ndash287 2005
[8] H Jafarzadeh M Sanatkhani and N Mohtasham ldquoOral pyo-genic granuloma a reviewrdquo Journal of Oral Science vol 48 no4 pp 167ndash175 2006
[9] T Nakamura ldquoApoptosis and expression of BaxBcl-2 proteinsin pyogenic granuloma a comparative study with granulationtissue and capillary hemangiomardquo Journal of Cutaneous Pathol-ogy vol 27 no 8 pp 400ndash405 2000
[10] K Yuan L-Y C Wing and M T Lin ldquoPathogenetic roles ofangiogenic factors in pyogenic granulomas in pregnancy aremodulated by female sex hormonesrdquo Journal of Periodontologyvol 73 no 7 pp 701ndash708 2002
[11] K Yuan and M T Lin ldquoThe roles of vascular endothelialgrowth factor and angiopoietin-2 in the regression of pregnancypyogenic granulomardquo Oral Diseases vol 10 no 3 pp 179ndash1852004
[12] F R Amaral V F Bernardes A P Duarte et al ldquoQuantitativeexpression analysis of apoptoticantiapoptotic genes and associ-ationwith immunolocalization of BAX andBCL-2 in peripheral
8 Journal of Oral Diseases
and central giant cell lesions of the jawsrdquo Tumor Biology vol 32no 5 pp 997ndash1003 2011
[13] J Pammer W Weninger H Hulla P Mazal and R HorvatldquoExpression of regulatory apoptotic proteins in peripheral giantcell granulomas and lesions containing osteoclast-like giantcellsrdquo Journal of Oral Pathology and Medicine vol 27 no 6 pp267ndash271 1998
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[15] T Honma T Saito and Y Fujioka ldquoPossible role of apoptoticcells of the oral epithelium in the pathogenesis of aphthousulcerationrdquoOral Surgery Oral Medicine and Oral Pathology vol59 no 4 pp 379ndash387 1985
[16] J F N Pinto Rodrigues C T Fujiyama Oshima A P RibeiroPaiotti M Franco S S Miki Ihara and D A RibeiroldquoExpression of apoptosis regulatory proteins p53 bcl-2 andbax in recurrent aphthous ulcerationrdquo Journal of the EuropeanAcademy of Dermatology and Venereology vol 26 no 10 pp1247ndash1251 2012
[17] J Gamonal A Bascones A Acevedo E Blanco and A SilvaldquoApoptosis in chronic adult periodontitis analyzed by in situDNA breaks electron microscopy and immunohistochem-istryrdquo Journal of Periodontology vol 72 no 4 pp 517ndash525 2001
[18] F Jarnbring E Somogyi J Dalton A Gustafsson and BKlinge ldquoQuantitative assessment of apoptotic and prolifera-tive gingival keratinocytes in oral and sulcular epithelium inpatients with gingivitis and periodontitisrdquo Journal of ClinicalPeriodontology vol 29 no 12 pp 1065ndash1071 2002
[19] P Kelk A Johansson R Claesson L Hanstrom and S KalfasldquoCaspase 1 involvement in human monocyte lysis induced byActinobacillus actinomycetemcomitans leukotoxinrdquo Infectionand Immunity vol 71 no 8 pp 4448ndash4455 2003
[20] P G Stathopoulou J C Galicia M R Benakanakere C AGarcia J Potempa and D F Kinane ldquoPorphyromonas gingi-valis induce apoptosis in human gingival epithelial cells througha gingipain-dependent mechanismrdquo BMC Microbiology vol 9article 107 2009
[21] T Murata K YaegakiW Qian et al ldquoHydrogen sulfide inducesapoptosis in epithelial cells derived from human gingivalrdquoJournal of Breath Research vol 2 no 1 Article ID 017007 2008
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[23] A Kantarci P Augustin E Firatli et al ldquoApoptosis in gingivalovergrowth tissuesrdquo Journal of Dental Research vol 86 no 9pp 888ndash892 2007
[24] VAMurrah andE PGilchrist ldquoAssessment of apoptosis in orallichen planusrdquoOral Surgery OralMedicine Oral Pathology OralRadiology and Endodontics vol 82 no 2 pp 209ndash210 1996
[25] M R Roopashree R V Gondhalekar M C Shashikanth JGeorge S H Thippeswamy and A Shukla ldquoPathogenesis oforal lichen planus a reviewrdquo Journal of Oral Pathology andMedicine vol 39 no 10 pp 729ndash734 2010
[26] R Mattila and S Syrjanen ldquoCaspase cascade pathways inapoptosis of oral lichen planusrdquo Oral Surgery Oral MedicineOral Pathology Oral Radiology and Endodontology vol 110 no5 pp 618ndash623 2010
[27] J M C Brant A C Vasconcelos and L V Rodrigues ldquoRole ofapoptosis in erosive and reticular oral lichen planus exhibiting
[28] B K Bloor F K Malik E W Odell and P R MorganldquoQuantitative assessment of apoptosis in oral lichen planusrdquoOral Surgery OralMedicine Oral Pathology Oral Radiology andEndodontics vol 88 no 2 pp 187ndash195 1999
[29] F A C G D Sousa T C Paradella Y R Carvalho and L EB Rosa ldquoImmunohistochemical expression of PCNA p53 baxand bcl-2 in oral lichen planus and epithelial dysplasiardquo Journalof oral science vol 51 no 1 pp 117ndash121 2009
[30] C Bascones-Ilundain M A Gonzalez-Moles G Esparza-Gomez J A Gil-Montoya and A Bascones-Martınez ldquoImpor-tance of apoptoticmechanisms in inflammatory infiltrate of orallichen planus lesionsrdquo Anticancer Research vol 26 no 1 pp357ndash362 2006
[31] V N Pimentel L S de Matos T C B Soares et al ldquoPerforinand granzyme B involvement in oral lesions of lichen planusand chronic GVHDrdquo Journal of Oral Pathology and Medicinevol 39 no 10 pp 741ndash746 2010
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[33] E Chrysomali F Lozada-Nur N P Dekker S I Papanicolaouand J A Regezi ldquoApoptosis in oral erythema multiformerdquo OralSurgery Oral Medicine Oral Pathology Oral Radiology andEndodontics vol 83 no 2 pp 272ndash280 1997
[34] R Abe T Shimizu A Shibaki H Nakamura HWatanabe andH Shimizu ldquoToxic epidermal necrolysis and Stevens-Johnsonsyndrome are induced by soluble fas ligandrdquo The AmericanJournal of Pathology vol 162 no 5 pp 1515ndash1520 2003
[35] S Inachi H Mizutani and M Shimizu ldquoEpidermal apop-totic cell death in erythema multiforme and Stevens-Johnsonsyndrome contribution of perforin-positive cell infiltrationrdquoArchives of Dermatology vol 133 no 7 pp 845ndash849 1997
[36] A K Vaishnaw E Toubi S Ohsako et al ldquoThe spectrumof apoptotic defects and clinical manifestations includingsystemic lupus erythematosus in humans with Cd95 (FasApo-1)mutationsrdquoArthritis and Rheumatism vol 42 no 9 pp 1833ndash1842 1999
[37] S White and A Rosen ldquoApoptosis in systemic lupus erythe-matosusrdquo Current Opinion in Rheumatology vol 15 no 5 pp557ndash562 2003
[38] D Shah S Sah and S K Nath ldquoInteraction between glu-tathione and apoptosis in systemic lupus erythematosusrdquoAutoimmunity Reviews vol 12 no 7 pp 741ndash751 2013
[39] S Rajagopalan E C Somers R D Brook et al ldquoEndothelial cellapoptosis in systemic lupus erythematosus a common pathwayfor abnormal vascular function and thrombosis propensityrdquoBlood vol 103 no 10 pp 3677ndash3683 2004
[40] M Bektas P Jolly and D S Rubenstein ldquoApoptotic pathwaysin pemphigusrdquo Dermatology Research and Practice vol 2010Article ID 456841 2010
[41] M Puviani A Marconi E Cozzani and C Pincelli ldquoFas ligandin pemphigus sera induces keratinocyte apoptosis through theactivation of caspase-8rdquo Journal of Investigative Dermatologyvol 120 no 1 pp 164ndash167 2003
[42] B H Roh K U Whang M K Cho Y L Park J S Lee andCW Lee ldquoA study of apoptosis in pemphigus vulgarisrdquo KoreanJournal of Dermatology vol 45 no 7 pp 650ndash658 2007
[43] P Deyhimi and P Tavakoli ldquoStudy of apoptosis in oral pem-phigus vulgaris using immunohistochemical marker Bax and
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TUNEL techniquerdquo Journal of Oral Pathology andMedicine vol42 no 5 pp 409ndash414 2013
[44] B Pelacho C Natal A Espana I Sanchez-Carpintero MJ Iraburu and M J Lopez-Zabalza ldquoPemphigus vulgarisautoantibodies induce apoptosis inHaCaT keratinocytesrdquo FEBSLetters vol 566 no 1ndash3 pp 6ndash10 2004
[45] K Yoneda T Furukawa Y-J Zheng et al ldquoAn autocrineparacrine loop linking keratin 14 aggregates to tumor necrosisdactor 120572-mediated cytotoxicity in a keratinocyte model ofepidermolysis bullosa simplexrdquo Journal of Biological Chemistryvol 279 no 8 pp 7296ndash7303 2004
[46] P P Sedghizadeh C M Allen K E Anderson D H Kim JR Kalmar and J C Lang ldquoOral graft-versus-host disease andprogrammed cell death pathogenetic and clinical correlatesrdquoOral Surgery OralMedicine Oral Pathology Oral Radiology andEndodontics vol 97 no 4 pp 491ndash498 2004
[47] T A Graubert J H Russell and T J Ley ldquoThe role of granzymeB in murine models of acute graft-versus-host disease and graftrejectionrdquo Blood vol 87 no 4 pp 1232ndash1237 1996
[48] N Zavazava and D Kabelitz ldquoAlloreactivity and apoptosisin graft rejection and transplantation tolerancerdquo Journal ofLeukocyte Biology vol 68 no 2 pp 167ndash174 2000
[49] A Sarin E KHaddad and PAHenkart ldquoCaspase dependenceof target cell damage induced by cytotoxic lymphocytesrdquo Jour-nal of Immunology vol 161 no 6 pp 2810ndash2816 1998
[50] M Enari H Hug and S Nagata ldquoInvolvement of an ICE-likeprotease in Fas-mediated apoptosisrdquo Nature vol 375 no 6526pp 78ndash81 1995
[51] T H Holmstrom and J E Eriksson ldquoPhophorylation basedsignaling in Fas receptor mediated apoptosisrdquo Critical Reviewsin Immunology vol 20 pp 121ndash152 2000
[52] Y H Yoo A C Gilliam D Whitaker-Menezes R Korngoldand G F Murphy ldquoExperimental induction and ultrastructuralcharacterization of apoptosis in marine acute cutaneous graft-versus-host diseaserdquo Archives of Dermatological Research vol289 no 7 pp 389ndash398 1997
[53] Y Hayashi K Yayagi and N Haneji ldquoInvolvement of apoptoticprotease cascade for tissue destruction in Sjogrenrsquos syndromerdquoArchivum Immunologiae et Therapiae Experimentalis vol 48no 5 pp 399ndash403 2000
[54] A I Bolstad and R Jonsson ldquoThe role of apoptosis in Sjogrenrsquossyndromerdquo Annals of Internal Medicine vol 149 no 1 pp 25ndash29 1998
[55] P Manganelli and P Fietta ldquoApoptosis and Sjogren syndromerdquoSeminars in Arthritis and Rheumatism vol 33 no 1 pp 49ndash652003
[56] M Ohlsson K Skarstein A I Bolstad A C Johannessen andR Jonsson ldquoFas-induced apoptosis is a rare event in Sjogrenrsquossyndromerdquo Laboratory Investigation vol 81 no 1 pp 95ndash1052001
[57] M Sisto S Lisi D Lofrumento M DrsquoAmore P Scagliusiand VMitolo ldquoAutoantibodies from Sjogrenrsquos syndrome triggerapoptosis in salivary gland cell linerdquo Annals of the New YorkAcademy of Sciences vol 1108 pp 418ndash425 2007
[58] L S Young C W Dawson and A G Eliopoulos ldquoViruses andapoptosisrdquo British Medical Bulletin vol 53 no 3 pp 509ndash5211997
[59] B M Polster J Pevsner and J M Hardwick ldquoViral Bcl-2homologs and their role in virus replication and associateddiseasesrdquo Biochimica et Biophysica Acta vol 1644 no 2-3 pp211ndash227 2004
[60] S Cooray ldquoThe pivotal role of phosphatidylinositol 3-kinase-Akt signal transduction in virus survivalrdquo Journal of GeneralVirology vol 85 no 5 pp 1065ndash1076 2004
[61] J G Teodoro andP E Branton ldquoRegulation of apoptosis by viralgene productsrdquo Journal of Virology vol 71 no 3 pp 1739ndash17461997
[62] M L Nguyen and J A Blaho ldquoApoptosis during herpes simplexvirus infectionrdquo Advances in Virus Research vol 69 pp 67ndash972006
[63] A Kather M J Raftery G Devi-Rao et al ldquoHerpes simplexvirus type 1 (HSV-1)-induced apoptosis in human dendriticcells as a result of downregulation of cellular FLICE-inhibitoryprotein and reduced expression of HSV-1 antiapoptotic latency-associated transcript sequencesrdquo Journal of Virology vol 84 no2 pp 1034ndash1046 2010
[64] L Aurelian ldquoHSV-induced apoptosis in herpes encephalitisrdquoCurrent Topics in Microbiology and Immunology vol 289 pp79ndash111 2005
[65] J Ennaciri J Menezes F Proulx and B J Toledano ldquoInductionof apoptosis by herpes simplex virus-1 in neonatal but not adultneutrophilsrdquo Pediatric Research vol 59 no 1 pp 7ndash12 2006
[66] A M Fuentes-Gonzalez A Contreras-Paredes J Manzo-Merino and M Lizano ldquoThe modulation of apoptosis byoncogenic virusesrdquo Virology Journal vol 10 article 182 2013
[67] MThomas and L Banks ldquoInhibition of Bak-induced apoptosisby HPV-18 E6rdquo Oncogene vol 17 no 23 pp 2943ndash2954 1998
[68] M Roshal Y Zhu and V Planelles ldquoApoptosis in AIDSrdquoApoptosis vol 6 no 1-2 pp 103ndash116 2001
[69] N W Cummins and A D Badley ldquoMechanisms of HIV-associated lymphocyte apoptosis 2010rdquo Cell Death and Diseasevol 1 no 11 article e99 2010
[70] A M Loyola S V Cardoso G S Lisa et al ldquoApoptosis inepithelial cells of apical radicular cystsrdquo International Endodon-tic Journal vol 38 no 7 pp 465ndash469 2005
[71] T Suzuki H Kumamoto K Kunimori andKOoya ldquoImmuno-histochemical analysis of apoptosis-related factors in liningepithelium of radicular cystsrdquo Journal of Oral Pathology andMedicine vol 34 no 1 pp 46ndash52 2005
[72] C A Martins E R C Rivero R M Dufloth C P Figueiredoand D S C Vieira ldquoImmunohistochemical detection of factorsrelated to cellular proliferation and apoptosis in radicular anddentigerous cystsrdquo Journal of Endodontics vol 37 no 1 pp 36ndash39 2011
[73] E Kichi Y Enokiya T Muramatsu et al ldquoCell proliferationapoptosis and apoptosis-related factors in odontogenic kerato-cysts and in dentigerous cystsrdquo Journal of Oral Pathology andMedicine vol 34 no 5 pp 280ndash286 2005
[74] A Piattelli M Fioroni and C Rubini ldquoDifferentiation ofodontogenic keratocysts from other odontogenic cysts by theexpression of bcl-2 immunoreactivityrdquo Oral Oncology vol 34no 5 pp 404ndash407 1998
[75] G C P Mateus G H D S P Lanza P H R deMoura H A deMarigo and M C R Horta ldquoCell proliferation and apoptosisin keratocystic odontogenic tumorsrdquo Medicina Oral PatologiaOral y Cirugia Bucal vol 13 no 11 pp E697ndashE702 2008
[76] L Artese A Piattelli C Rubini et al ldquop16 expression inodontogenic tumorsrdquo Tumori vol 94 no 5 pp 718ndash723 2008
[77] L Lo Muzio S Staibano G Pannone et al ldquoExpression of cellcycle and apoptosis-related proteins in sporadic odontogenickeratocysts and odontogenic keratocysts associated with thenevoid basal cell carcinoma syndromerdquo Journal of DentalResearch vol 78 no 7 pp 1345ndash1353 1999
10 Journal of Oral Diseases
[78] D K Kim S G Ahn J Kim and J H Yoon ldquoComparativeKi-67 expression and apoptosis in the odontogenic keratocystassociated with or without an impacted tooth in addition tounilocular and multilocular varietiesrdquo Yonsei Medical Journalvol 44 no 5 pp 841ndash846 2003
[79] M Andric B Dozic B Popovic et al ldquoSurvivin expression inodontogenic keratocysts and correlation with cytomegalovirusinfectionrdquo Oral Diseases vol 16 no 2 pp 156ndash159 2010
[80] I R H Kramer J J Pindborg and M ShearWHOHistologicalTyping of Odontogenic Tumours Springer Berlin Germany1992
[81] H Kumamoto and K Ooya ldquoDetection of mitochondria-mediated apoptosis signaling molecules in ameloblastomasrdquoJournal of Oral Pathology and Medicine vol 34 no 9 pp 565ndash572 2005
[82] H Kumamoto and K Ooya ldquoImmunohistochemical detectionof BH3-only proteins in ameloblastic tumorsrdquo Oral Diseasesvol 14 no 6 pp 550ndash555 2008
[83] H Kumamoto and K Ooya ldquoExpression of tumor necrosisfactor120572 TNF-related apoptosis-inducing ligand and their asso-ciated molecules in ameloblastomasrdquo Journal of Oral Pathologyand Medicine vol 34 no 5 pp 287ndash294 2005
[84] H Kumamoto K Kimi and K Ooya ldquoImmunohistochemicalanalysis of apoptosis-related factors (Fas Fas ligand caspase-3and single-stranded DNA) in ameloblastomasrdquo Journal of OralPathology and Medicine vol 30 no 10 pp 596ndash602 2001
[85] T E Carneiro S A Marinho F D Verli A T M Mesquita NL Lima and J L Miranda ldquoOral squamous papilloma clinicalhistologic and immunohistochemical analysesrdquo Journal of oralscience vol 51 no 3 pp 367ndash372 2009
[86] T Yamaguchi M Shindoh A Amemiya et al ldquoDetectionof human papillomavirus type 2 related sequence in oralpapillomardquo Analytical Cellular Pathology vol 16 no 3 pp 125ndash130 1998
[87] J H Main and M Pavone ldquoActinic cheilitis and carcinoma ofthe liprdquo Journal of Canadian Dental Association vol 60 no 2pp 113ndash116 1994
[88] A Martınez U Brethauer I G Rojas et al ldquoExpression ofapoptotic and cell proliferation regulatory proteins in actiniccheilitisrdquo Journal of Oral Pathology and Medicine vol 34 no5 pp 257ndash262 2005
[89] M A Birchall C MWinterford D J Allan and B V HarmonldquoApoptosis in normal epithelium premalignant and malignantlesions of the oropharynx and oral cavity a preliminary studyrdquoEuropean Journal of Cancer B vol 31 no 6 pp 380ndash383 1995
[90] N Tanda S Mori K Saito K Ikawa and S SakamotoldquoExpression of apoptotic signaling proteins in leukoplakia andoral lichen planus quantitative and topographical studiesrdquoJournal of Oral Pathology and Medicine vol 29 no 8 pp 385ndash393 2000
[91] G Kovesi and B Szende ldquoProgression of the leukoplakia isassociated to changes in apoptotic and mitotic index as well asin p53 and Ki-67 expressionrdquo Oncology vol 46 no 4 pp 333ndash338 2002
[92] H Tsuzuki S Fujieda H Sunaga N Narita M Tokuriki andH Saito ldquoExpression of p27 and apoptosis in oral leukoplakiardquoAnticancer Research vol 23 no 2 pp 1265ndash1270 2003
[93] E Chrysomali J S Greenspan N Dekker D Greenspanand J A Regezi ldquoApoptosis-associated proteins in oral hairyleukoplakiardquo Oral Diseases vol 2 no 4 pp 279ndash284 1996
[94] S H Kaufmann andG J Gores ldquoApoptosis in cancer cause andcurerdquo BioEssays vol 22 pp 1007ndash1017 2000
[95] S Ghavami M Hashemi S R Ande et al ldquoApoptosis andcancer mutations within caspase genesrdquo Journal of MedicalGenetics vol 46 no 8 pp 497ndash510 2009
[96] C M Coutinho-Camillo S V Lourenco I N NishimotoL P Kowalski and F A Soares ldquoCaspase expression in oralsquamous cell carcinomardquo Head and Neck vol 33 no 8 pp1191ndash1198 2011
[97] P J Polverini and J E Nor ldquoApoptosis and predisposition tooral cancerrdquo Critical Reviews in Oral Biology and Medicine vol10 no 2 pp 139ndash152 1999
[98] M Sulkowska W Famulski S Sulkowski et al ldquoCorrelationbetween Bcl-2 protein expression and some clinicopathologicalfeatures of oral squamous cell carcinomardquo Polish Journal ofPathology vol 54 no 1 pp 49ndash52 2003
[99] L L Loro O K Vintermyr P G Liavaag R Jonsson and A CJohannessen ldquoOral squamous cell carcinoma is associated withdecreased bcl-2bax expression ratio and increased apoptosisrdquoHuman Pathology vol 30 no 9 pp 1097ndash1105 1999
[100] M Baltaziak M KodaM Barwijuk-Machała et al ldquoThe role ofBak expression in apoptosis of the oral squamous cell carcinoma(OSCC) and metastases to lymph nodes (LNMs)rdquo AnnalesAcademiae Medicae Bialostocensis vol 49 pp 14ndash15 2004
[101] J C de Vicente L M J Gutierrez A H Zapatero M FF Forcelledo G Hernandez-Vallejo and J S Lopez ArranzldquoPrognostic significance of p53 expression in oral squamous cellcarcinoma without neck node metastasesrdquo Head and Neck vol26 no 1 pp 22ndash30 2004
[102] M A Gonzalez-Moles P Galindo J Gutierrez-Fernandez etal ldquoP53 protein expression in oral squamous cell carcinomasurvival analysisrdquo Anticancer Research vol 21 no 4 pp 2889ndash2894 2001
[103] S Kannan G Jagadeesh Chandran K Raveendran Pillai et alldquoExpression of p53 in leukoplakia and squamous cell carcinomaof the oral mucosa correlation with expression of Ki67rdquo Journalof Clinical Pathology vol 49 no 3 pp M170ndashM175 1996
[104] J Y Koh N P Cho G Kong J D Lee and K Yoon ldquop53mutations and human papillomavirus DNA in oral squamouscell carcinoma correlation with apoptosisrdquo British Journal ofCancer vol 78 no 3 pp 354ndash359 1998
[105] L LoMuzio G Pannone S Staibano et al ldquoSurvivin expressionin oral squamous cell carcinomardquo British Journal of Cancer vol89 no 12 pp 2244ndash2248 2003
[106] Y Jinbu K Tsukinoki N Miyagi et al ldquoExpression of survivinin oral squamous cell carcinomardquo Oral Med Pathol vol 11 pp41ndash44 2006
[107] C Jane A V Nerurkar N V Shirsat R B DeshpandeA D Amrapurkar and F R Karjodkar ldquoIncreased survivinexpression in high-grade oral squamous cell carcinoma a studyin Indian tobacco chewersrdquo Journal of Oral Pathology andMedicine vol 35 no 10 pp 595ndash601 2006
[108] Y-H Kim S-M Kim Y-K Kim S-P Hong M-J Kim andH Myoung ldquoEvaluation of survivin as a prognostic marker inoral squamous cell carcinomardquo Journal of Oral Pathology andMedicine vol 39 no 5 pp 368ndash375 2010
[109] N G Nikitakis J J Sauk and S I Papanicolaou ldquoThe role ofapoptosis in oral disease mechanisms aberrations in neoplas-tic autoimmune infectious hematologic and developmentaldiseases and therapeutic opportunitiesrdquo Oral Surgery OralMedicine Oral Pathology Oral Radiology and Endodontics vol97 no 4 pp 476ndash490 2004
[110] L L Loro O K Vintermyr A C Johannessen P G Liavaagand R Jonsson ldquoSuppression of Fas receptor and negative
Journal of Oral Diseases 11
correlation of Fas ligand with differentiation and apoptosis inoral squamous cell carcinomardquo Journal of Oral Pathology andMedicine vol 28 no 2 pp 82ndash87 1999
[111] N H Al-Rawi H Omer and S Al Kawas ldquoImmunohistochem-ical analysis of P53 and bcl-2 in benign and malignant salivaryglands tumorsrdquo Journal of Oral Pathology and Medicine vol 39no 1 pp 48ndash55 2010
[112] ANordkvist E Roijer G Bang et al ldquoExpression andmutationpatterns of p53 in benign andmalignant salivary gland tumorsrdquoInternational Journal of Oncology vol 16 no 3 pp 477ndash4832000
[113] V J Karja K J Syrjanen A-K Kurvinen and S M SyrjanenldquoExpression and mutations of p53 in salivary gland tumoursrdquoJournal of Oral Pathology and Medicine vol 26 no 5 pp 217ndash223 1997
[114] M Yanezez I Roa M Garcıa G Ibacache and M VillasecaldquoGene Bcl-2 protein expression in salivary gland tumorsrdquoRevista Medica de Chile vol 127 no 2 pp 139ndash142 1999
[115] L Jia R L Esguerra X Tang et al ldquoPrognostic value ofapoptosis and apoptosis-associated proteins in salivary glandadenoid cystic carcinomardquo Pathology International vol 54 no4 pp 217ndash223 2004
[116] Y Soini U Tormanen and P Paakko ldquoApoptosis is inverselyrelated to bcl-2 but not to bax expression in salivary glandtumoursrdquo Histopathology vol 32 no 1 pp 28ndash34 1998
[117] R M Nagler H Kerner S Ben-Eliezer I Minkov and O Ben-Itzhak ldquoPrognostic role of apoptotic Bcl-2 c-erbB-2 and p53tumor markers in salivary gland malignanciesrdquo Oncology vol64 no 4 pp 389ndash398 2003
abnormal vascular function and elevated tissue factor levelsandmay represent an importantmechanism for developmentof atherothrombosis in SLE [39]
334 Apoptosis and Pemphigus Vulgaris Pemphigus is agroup of autoimmune blistering diseases characterized byloss of keratinocyte cell adhesion that leads to clinical blisterformation Induction of apoptosis or of proapoptotic proteinsby pemphigus IgGmay be (i) part of themechanism bywhichsera and IgG induce acantholysis or (ii) a consequence of lossof adhesion (anoikis) and a result of acantholysis [40] Fasligand levels are markedly increased in sera from untreatedpemphigus patients which is suggesting that FasFas lig-and cell death pathway plays amajor role in anoikis as seen inpemphigus [41] Hoechst 33342 staining andRT-PCR analysisshowed that apoptosis may be associated with acantholysisof pemphigus lesional epidermis and may play an importantrole in the pathogenesis of pemphigus [42] Apoptosis isobserved in the perilesional normal appearing tissue sug-gesting that it is an early phenomenon Also the process ofapoptosis may cause exacerbation or speeding of the bullaformation [43] But whether apoptosis is really essential foracantholysis in pemphigus is not clear Immunofluorescenceanalysis confirmed that PV IgG autoantibodies promoteapoptosis in HaCaT keratinocytes characterized by caspase-3activation Bcl-2 depletion and Bax expression [44]
335 Apoptosis and Epidermolysis Bullosa Epidermolysisbullosa is a hereditary vesiculobullous disease characterizedby blistering of the skin and oral mucosa due to basalkeratinocyte fragility [7] Experiment using cellular model ofEBS showed thatHaCaT cells were susceptible to apoptosis byactivation of caspases 3 and 8 but not caspase-9 or caspase-12 Moreover TNF-120572 release and the subsequent activationof the TNF-120572 receptor by an autocrineparacrine pathwaylink protein aggregates to cell death in this keratinocyteEBS cellular model Also susceptibility of keratinocytes tocaspase-8-mediated apoptosis is increased in mutated K14because of impairment of the cytoprotective mechanismmediated by K14-TRADD interaction [45]
336 Apoptosis and Oral Graft-versus-Host Diseases Graft-versus-host disease (GVHD) is characterized by an immune-mediated attack by donor immune cells against variousrecipient host cells and tissues Although donor and recip-ient are matched at major histocompatibility loci prior totransplantation GVHD occurs because differences exist atminor histocompatibility loci Programmed cell death orapoptosis has been evidenced as major constituent in thepathogenesis of GVHD Oral involvementmay be seen in 33ndash75 of patients who develop acute GVHD and in up to 80of patients affected by chronic GVHD making these lesionsuseful as a highly predictive index for the presence of systemicdisease The oral lesions of GVHD are clinically and histo-logically lichenoid in nature [46] CTL mediated apoptoticpathway predominates in GVHD Initiation can occur eitherwhen virus-specific cytotoxic T lymphocytes (CTL) bind totarget cells and release granzymes into the cells or when CTL
bind and activate the TNF family of receptors such as the Fas-receptor or TRAIL-receptor [46ndash48] Caspases and severalintracellular proteases participate in propagating and actuat-ing the apoptotic death signal through a proteolytic cleavagecascade [49 50] Phosphorylation pathways regulate signaltransduction cascades [51] However experimental murinemodels of acute GVHD demonstrated that apoptosis can beinduced even in the absence of immune cells suggestingexistence of an additional mechanism for target cell injury[52]
337 Apoptosis and Sjogrenrsquos Syndrome Sjogrenrsquos syndrome(SS) is an autoimmune disease characterized by diffuselymphoid cell infiltrates in the salivary and lacrimal glandsresulting in symptoms of dry mouth and eyes [53] Threeaspects of apoptosis are related to SS (i) defective apopto-sis could lead to lymphoid cell accumulation and chronicinflammation in exocrine glands (ii) increased apoptosis ofepithelial cells might explain the loss of secreting epitheliumand (iii) orderly destruction of cellular components mightinduce autoantibody production [54] Apoptosis of the acinarand ductal epithelial cells of the salivary and lacrimal glandsmay be induced by either CTL through the release perforinand granzyme B or the interaction of Fas ligand expressedby T lymphocytes with Fas on epithelial cells [55] On thecontrary others believed that Fas-induced apoptosis amongSS salivary glands is a rare event despite their abundantexpression since infiltratingmononuclear cells seem to escapeapoptosis resulting in foci of inflammatory cells [56] 120 kDa120572-Fodrin is an important autoantigen in the developmentof SS in animal models and SS patients Anti-Fas antibody-induced apoptosis and an increase in the activities of calpainand caspases may be involved in the progression of 120572-fodrin proteolysis and tissue destruction in the developmentof SS [53] In vitro analysis demonstrated that apoptosistriggered by anti-Ro and anti-La could be responsible for theimpairment of the secretory function in the salivary glands[57]
34 Apoptosis and Virus Associated Diseases Various typesof viruses have been involved in the pathogenesis of dif-ferent oral lesions the commonest being herpes simplexvirus (HSV) human papillomaviruses (HPV) and humanimmunodeficiency virus (HIV) Virus infected cells can oftenbe recognized and destroyed by apoptotic processes initiatedby either CTL or certain cytokines Many viruses directlyinduce apoptosis during infection which is at least partiallyresponsible for the various viral pathologies Many viruseshave evolved with multiple distinct mechanisms to blockthe premature apoptosis of infected cells either facilitatingthe maintenance of persistent infection or prolonging thesurvival of lytically infected cells such that the production ofprogeny virus is maximized [58] Examples include blockageof apoptosis by viral BCL-2 (vBCL-2) homologues [59] uti-lization of the phosphatidylinositol 3-kinase-Akt signallingpathway [60] or suppression of inducers of apoptosis suchas p53 [61]
HSV infection triggers apoptosis in infected cells How-ever proteins synthesized later in infected cells prevent
Journal of Oral Diseases 5
apoptotic cell death from ensuingThis apoptoticmodulationhas a role in the development of herpetic disease [62] HSV-1-induced apoptosis of immature dendritic cells is associatedwith downregulation of the cellular FLICE-inhibitory protein(c-FLIP) in a proteasome-independent manner [63] HSV-1triggers apoptosis in CNS neurons and causes encephalitis inadult subjects [64] HSV-1 enhances apoptosis via expressionof both Fas and Fas ligand on the surface of neonatalneutrophils [65]
High risk HPV oncoproteins E6 E7 and E5 can mod-ulate host mediated apoptosis by inhibiting death receptorsignaling and thus regulate the survival of infected cells [66]HPV E6 proteins inhibit apoptosis in both p53-dependentand p53-independent manners HPV-18 E6 inhibits Bak-induced apoptosis in differentiating keratinocytes in whichHPV replicates It was also suggested that Bak is probably thefirst naturally occurring target of ubiquitin ligase E6AP [67]
HIV infection usually leads to progressive immunod-eficiency and loss of immune competence associated withdeclines in both the functionality and the number of CD4+lymphocytes which in turn is related to various viral andimmunological processes Proposed virus-mediated mech-anisms include toxicity caused by accumulation of uninte-grated viral DNA alteration in membrane permeability dueto budding of viral particles and terminal differentiationAmong the immunological mechanisms are killing by spe-cific CTL and signaling through the CD4 molecule leadingto CD4+ lymphocytes apoptosis [68] Apoptosis in HIV maybe stimulated by environmental stress toxins and removalof growth factors and may be mediated by one of thesedeath inducing ligands TNF FasL and TRAIL [69] Manyof the proteins that are encoded by the HIV genome havebeen found to have pro- andor antiapoptotic qualities HIVsurface glycoprotein gp120 cross-links CD4 and primes cellsfor apoptosis HIV-1 can also induce apoptosis ldquofrom withinrdquovia expression of certain viral genes such as tat nef vpu andvpr [68 69]
35 Apoptosis and Benign Entities
351 Apoptosis and Benign Odontogenic Cysts and Tumors
(1) Apoptosis and RadicularApical Cyst Radicular cysts arethe most common cystic lesions of the jaws and representa periapical inflammatory disease evoked by infected andnecrotic dental pulp Apoptosis was found to be alwayspresent in the epithelium of the apical radicular cyst Higherapoptotic index (AI) and bcl-2 index (bcl-2I) were found inlesions with atrophic compared to hyperplastic epitheliumbut the difference was statistically insignificant However apositive and significant correlation was found between AIand bcl-2I [70] Epithelium of radicular and residual cystsshowed expression of apoptosis related factors like ssDNAp53 Bax Bcl-2 caspase-3 Fas Fas-L and Ki-67 antigensuggesting their role in the pathophysiologic activity ofperiapical inflammatory lesions Such factors may be affectedby the structure of lining epithelium and the degree ofinflammatory change since Ki-67 and ssDNA reactivity inRCs with intense inflammatory reactions or with thick lining
epithelium were significantly stronger than those RCs withless inflammation or with thin lining [71] Caspase-3 andKi-67 expression was significant in hyperplastic epitheliumrelated to intense inflammation whereas Bcl-2 expressionwas significantly higher in atrophic epithelium of DCs thanRCs suggesting that although they may have different patho-genetic mechanism they have similar biological behavior inthe presence of intense inflammatory infiltrate [72]
(2) Apoptosis and Dentigerous Cyst The epithelial lining ofDCs has shown TUNEL Ki-67 and p53 positivity but theexpression was weak as compared to OKCs indicating thatapoptosis is involved in cyst formation and maintainingthe regular thickness of the lining epithelium in DCs [73]Bcl-2 positivity was significantly higher in atrophic epithe-lium of DCs than that of RCs suggesting that presence ofinflammation inhibits the Bcl-2 expression and both cystshave similar biological behavior in the presence of intenseinflammatory infiltrate [72] whereas other demonstrated thatBcl-2 expression was almost completely negative in DCs andRCs compared to OKCs [74]
(3) Apoptosis and Odontogenic KeratocystKeratocystic Odon-togenic Tumor Keratocystic odontogenic tumor (KCOT)also known as odontogenic keratocyst (OKC) was recentlyclassified as a benign neoplasia due to the aggressive clinicalbehavior The proliferation index and apoptotic index werefound to be higher and with distinct pattern in both sporadicand nevoid basal cell carcinoma syndrome (NBCCS) KCOTscompared to DCs reflecting its high cell turnover andreinforcing its classification as an odontogenic tumor [75]Lack of p16 expression in KCOT compared to strong ormoderate p16 expression in RCs and follicular cysts couldbe related to the increased aggressive behavior invasivenessand high frequency of recurrences found in KCOT [76]Overexpression of cyclin Dl and p53 in syndromic OKCscould be considered as hallmark of a mutated cellular phe-notype and more aggressive clinical behaviour compared tosporadic KCOTs which were negative for these oncoproteins[77] Strong Bcl-2 overexpression in OKCs suggests its rolein extension of cell survival leading to the peculiar aggressivegrowth pattern and can be useful to differentiate OKC fromother odontogenic cysts [74] TUNEL positive cells wereobserved in the surface layers of OKCs whereas no positivitywas seen in the basal or intermediate layers of OKCs andDCs Also Ki67-positive ratio and p53-positive ratio in theintermediate layer were the highest in OKCs and Bcl-2-positive cells were discernible exclusively in the basal layerof OKCs signifying that subsequently OKCs are seen ascystic lesions but not as tumor masses [73] There is nosignificant difference in proliferative activity and apoptosisin OKCs associated with or without impacted teeth orbetween the unilocular ormultilocular variants [78] Survivinimmunoexpression was positive in all cases of OKCs while allperiapical cysts were negative suggesting its contribution toviolent behavior of OKCs [79]
(4) Apoptosis and Ameloblastomas Ameloblastoma isthe most frequently encountered tumor arising from
6 Journal of Oral Diseases
odontogenic epithelium and is characterized by a benign butlocally invasive behavior with a high risk of recurrence [80]
RT-PCR and IHC showed expression of cytochrome cAPAF-1 caspase-9 and AIF in tooth germs and benign andmalignant ameloblastomas suggesting that themitochondria-mediated apoptotic pathway has a role in apoptotic celldeath of normal and neoplastic odontogenic epithelium andmight be involved in oncogenesis cytodifferentiation andmalignant transformation of odontogenic epithelium [81]
Granular cells basal cells desmoplastic ameloblastomasand ameloblastic carcinomas showed immunoreactivity forthe BH3-only proteins (Bid Bim Bad Noxa and Puma)whereas keratinising cells of acanthomatous ameloblastomasshowed no reactivity suggesting that these proteins mightbe involved in tumor cell differentiation of ameloblastomas[82] TNF-120572 TRAIL and their receptors were also found tobe expressed in tooth germs and ameloblastomas provingtheir role in cytodifferentiation of odontogenic epitheliumand tissue structuring of ameloblastomas [83] Similarlyexpression of Fas FasL caspase-3 and ssDNA has also beendemonstrated in various patterns in tooth germs and benignand malignant ameloblastomas [84]
352 Apoptosis and Benign Epithelial Tumor
(1) Apoptosis and Squamous PapillomaOral squamous papil-loma (OSP) is a frequent benign tumorous lesion associatedwith HPV OSP consists of proliferation of the stratifiedsquamous epithelium resulting in a papillary or verrucousexophytic mass and has got site predilection for the tongueand soft palate but any surface of the oral cavity can beaffected [85 86] Carneiro et al performed immunohisto-chemical assay on 12 OSP cases utilizing BP53-12 and Pab240antibodies for p53 protein and found that immunostainingfor protein p53 was primarily negative or weakly positivein all cases (in all epithelial layers) except one case whichindicates the benign nature of the lesions evidenced by theirslow development and less chances of becoming malignantIntense staining in one slide for both immunomarkers in allthe epithelial layers could be attributed to the presence ofvirus with high oncogenic potential (HPV 16 and 18) or tothe presence of coexisting external factors [85]
36 Apoptosis and Premalignant and Malignant Entities
361 Apoptosis and Actinic Cheilitis Actinic cheilitis (AC) isa common condition caused by damage to the lips throughexposure to sunlight and has the potential to undergomalignant transformation into squamous cell carcinoma [87]Overexpression of p53 was found in AC as compared tonormal lip and oral mucosa Bcl-2 expression was higherin AC than in oral mucosa but it was significantly reducedas compared with normal lip Thus it was suggested thatDNA-damaged cells by UV radiation in AC are eliminatedby apoptosis Also both p53 and bcl-2 play an important rolein regulating malignant transformation in AC [88]
362 Apoptosis and Oral Leukoplakia It has been sug-gested that a change in apoptosis accompanies the onset
of invasion in a premalignant lesion of the human oralcavity and oropharynx AI increased progressively fromnormal to carcinoma in situ (CIS) but fell in SCC withmaximum apoptotic index (AI) mitotic index (MI) ratioin CIS The position of apoptotic bodies was localised tothe deepest layers in normal and dysplastic epithelia butbecame generalised in CIS and SCC [89] Greater expressionof oncoproteins MDM2 and Bcl-2 was seen in leukoplakiawith altered keratinocyte maturation than OLP case whereasexpression of wt-p53 and p21 was higher in OLP compared toleukoplakia cases In spite of divergent outcome of apoptoticsignalling proteins no significant difference in the number ofapoptotic epithelial cells was observed between leukoplakiaand OLP cases [90] Increased mitotic apoptotic and Ki-67 index indicate unfavourable prognosis of leukoplakia [91]Abundance of p27 expression in oral leukoplakia may beassociated with inhibition of cell proliferation leading toapoptosis of premalignant tumor cells thus preventing tumorprogression [92] It is hypothesised that the antiapoptoticability of Epstein-Barr virus (EBV) may result in alteredexpression of apoptosis-associated proteins in oral hairyleukoplakia Except p53 which appears to be overexpressedthere is only slight alteration in immunoexpression of otherapoptosis-associated proteins in OHL [93]
363 Apoptosis and Oral Squamous Cell Carcinoma Theaccumulation of neoplastic cells can occur through enhancedproliferation diminished cell turnover or a combination ofboth processes Tumor cells from a wide variety of humancancers have been shown to exhibit increased survival andresistance to apoptosis [94] There are two major ways thatcould downregulate cancer cell apoptosis (1) somatic andnonsomatic mutation and loss of expression of proapoptoticmolecules and (2) overexpression of apoptosis inhibitorymolecules Mutations within caspase family proteases are notuncommon in malignancies [95] Caspase-7 proved to bean independent prognosticator and predictor of locoregionalrecurrence in patients of OSCC [96] Several alterations thatinhibit both the death receptor and mitochondrial pathwaysvia caspases have also been identified including overexpres-sion of IAPs activation of PI3k or Akt and posttranslationalmodifications of caspases [94]
In pathological settings Bcl-2 gene family appears toact synergistically with oncogenes and tumor suppressorgenes [97] Positive Bcl-2 expression is associated with highertumor grading higher tumor mitotic index higher index ofatypical mitoses and microfocal pattern of tumor invasivemargins [98] In OSCC compared with oral epitheliumthere is a decreased Bcl-2 expression a lowered Bcl-2Baxratio and increased apoptosis Expression of Bax correlatedwith histological tumor grading in OSCC [99] whereasothers found that expression of Bak may be useful for bettercharacterizing and predicting the prognosis of OSCC [100]
Aberrations of the p53 gene and overexpression of its pro-tein are widely recognized markers of malignancy includingOSCC It was found that there is a negative correlation of p53immunoexpression with histologic grade of differentiationIn patients without neck node metastases p53 showed astrong correlation with survival [101] On the contrary
Journal of Oral Diseases 7
another study showed that expression of p53 protein did notbehave as amarker of prognostic value in patients withOSCC[102]
As cancer is characterized by uncontrolled cell prolif-eration markers of proliferation such as Ki67 and PCNAhave been studied extensively in neoplastic lesions Expres-sion of both p53 and Ki67 correlated significantly with thehistopathological stage of the tumor However expression ofp53 was not correlated with that of Ki67 [103]
HPV infection andor p53 mutations are implicated incarcinogenesis of oral SCC but are not mutually exclusiveevents Moreover decrease in apoptosis is more closelyrelated to p53 mutation than HPV infection [104]
Survivin has got a versatile role in modulating celldivision and apoptosis in cancer Low survivin expressioncorrelated statistically significantly with better survival ratesbut not with age sex tumor size the presence of lymphnode or distant metastases [105] Survivin was found tobe preferentially expressed in nonadvanced nonmetastaticand chemotherapy-sensitive OSCC [106] On the contraryincreased expression of survivin was found in high-gradetumors suggesting its contribution to apoptosis resistancein response to therapy [107] Also significant correlationbetween survivin expression lymph node metastasis andproliferation was revealed but not with differentiationmicrovessel density or TNM staging [108]
Upregulation of FasL and downregulation of Fas havebeen shown to occur in oral carcinogenesis possibly con-tributing to both cancer cell survival and evasion of the hostimmune assault through induction of apoptosis in T cellsthat would normally kill tumor cells [109] Moreover it hasbeen found that Fas is expressed in low quantities in OSCCwhereas FasL expression correlates negatively with degree ofdifferentiation and apoptosis in OSCC [110] Thus variousproteins (apoptotic and antiapoptotic) have got a significantbearing in initiation progression and prognosis of OSCC
37 Apoptosis and Salivary Gland Tumors Salivary glandtumors (SGT) are relatively uncommon neoplasms withwidely variable histopathologic and biologic characteristicsP53bcl-2 immunostaining reactivity could be helpful indemonstrating SGT behavior in terms of progression andextent of invasion since all malignant salivary gland tumorswere positive whereas 70 of pleomorphic adenomas (PA)showed negative expression [111] Similarly Nordkvist et alfound p53 overexpression in 20 of the malignant SGT withthe highest prevalence in PLGA squamous cell carcinomaand CaXPA and the lowest in adenoid cystic carcinomaand acinic cell carcinoma but none of the benign PA [112]Expression of p53 in malignant tumors bore no correlationto local recurrence metastatic disease or survival of thepatients [113] Bcl-2 protein expression was found virtuallyin all benign and malignant SGT suggesting its role in thedevelopment and proliferation of these tumors via inhibitionof apoptosis [114] p53 expression apoptotic index and bcl-2 protein are potential prognostic parameters in salivarygland adenoid cystic carcinoma [115] Frequency of apoptosisis inversely related to bcl-2 but not to Bax expression inSGT [116] Survival probability of patients who demonstrated
positive staining for c-erbB-2 or TUNEL or both was lowerthan those with negative staining [117]
4 Conclusion
Understanding the mechanistic machinery of apoptosis iscrucial because it influences both health and disease beinginitiated by various physiologic and pathologic stimuliMore-over the extensive involvement of apoptosis in the patho-genesis of various oral diseases and meticulous knowledgeabout it prompt it to therapeutic intervention at differentcheckpoints This review is an attempt to provide an updateon the crucial role and importance of apoptosis in various oralpathologies
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] A Lawen ldquoApoptosis an introductionrdquo BioEssays vol 25 no 9pp 888ndash896 2003
[2] J F Kerr A H Wyllie and A R Currie ldquoApoptosis abasic biological phenomenon with wide-ranging implicationsin tissue kineticsrdquo British Journal of Cancer vol 26 no 4 pp239ndash257 1972
[3] A Strasser L OrsquoConnor and V M Dixit ldquoApoptosis signalingrdquoAnnual Review of Biochemistry vol 69 pp 217ndash245 2000
[4] N Singh ldquoApoptosis in health and disease and modulation ofapoptosis for therapy an overviewrdquo Indian Journal of ClinicalBiochemistry vol 22 no 2 pp 6ndash16 2007
[5] T-J Fan L-H Han R-S Cong and J Liang ldquoCaspase familyproteases and apoptosisrdquo Acta Biochimica et Biophysica Sinicavol 37 no 11 pp 719ndash727 2005
[6] P C Ashe and M D Berry ldquoApoptotic signaling cascadesrdquoProgress in Neuro-Psychopharmacology and Biological Psychia-try vol 27 no 2 pp 199ndash214 2003
[7] L L Loro O K Vintermyr and A C Johannessen ldquoApoptosisin normal and diseased oral tissuesrdquoOral Diseases vol 11 no 5pp 274ndash287 2005
[8] H Jafarzadeh M Sanatkhani and N Mohtasham ldquoOral pyo-genic granuloma a reviewrdquo Journal of Oral Science vol 48 no4 pp 167ndash175 2006
[9] T Nakamura ldquoApoptosis and expression of BaxBcl-2 proteinsin pyogenic granuloma a comparative study with granulationtissue and capillary hemangiomardquo Journal of Cutaneous Pathol-ogy vol 27 no 8 pp 400ndash405 2000
[10] K Yuan L-Y C Wing and M T Lin ldquoPathogenetic roles ofangiogenic factors in pyogenic granulomas in pregnancy aremodulated by female sex hormonesrdquo Journal of Periodontologyvol 73 no 7 pp 701ndash708 2002
[11] K Yuan and M T Lin ldquoThe roles of vascular endothelialgrowth factor and angiopoietin-2 in the regression of pregnancypyogenic granulomardquo Oral Diseases vol 10 no 3 pp 179ndash1852004
[12] F R Amaral V F Bernardes A P Duarte et al ldquoQuantitativeexpression analysis of apoptoticantiapoptotic genes and associ-ationwith immunolocalization of BAX andBCL-2 in peripheral
8 Journal of Oral Diseases
and central giant cell lesions of the jawsrdquo Tumor Biology vol 32no 5 pp 997ndash1003 2011
[13] J Pammer W Weninger H Hulla P Mazal and R HorvatldquoExpression of regulatory apoptotic proteins in peripheral giantcell granulomas and lesions containing osteoclast-like giantcellsrdquo Journal of Oral Pathology and Medicine vol 27 no 6 pp267ndash271 1998
[14] C Scully and S Porter ldquoOral mucosal disease recurrentaphthous stomatitisrdquo British Journal of Oral and MaxillofacialSurgery vol 46 no 3 pp 198ndash206 2008
[15] T Honma T Saito and Y Fujioka ldquoPossible role of apoptoticcells of the oral epithelium in the pathogenesis of aphthousulcerationrdquoOral Surgery Oral Medicine and Oral Pathology vol59 no 4 pp 379ndash387 1985
[16] J F N Pinto Rodrigues C T Fujiyama Oshima A P RibeiroPaiotti M Franco S S Miki Ihara and D A RibeiroldquoExpression of apoptosis regulatory proteins p53 bcl-2 andbax in recurrent aphthous ulcerationrdquo Journal of the EuropeanAcademy of Dermatology and Venereology vol 26 no 10 pp1247ndash1251 2012
[17] J Gamonal A Bascones A Acevedo E Blanco and A SilvaldquoApoptosis in chronic adult periodontitis analyzed by in situDNA breaks electron microscopy and immunohistochem-istryrdquo Journal of Periodontology vol 72 no 4 pp 517ndash525 2001
[18] F Jarnbring E Somogyi J Dalton A Gustafsson and BKlinge ldquoQuantitative assessment of apoptotic and prolifera-tive gingival keratinocytes in oral and sulcular epithelium inpatients with gingivitis and periodontitisrdquo Journal of ClinicalPeriodontology vol 29 no 12 pp 1065ndash1071 2002
[19] P Kelk A Johansson R Claesson L Hanstrom and S KalfasldquoCaspase 1 involvement in human monocyte lysis induced byActinobacillus actinomycetemcomitans leukotoxinrdquo Infectionand Immunity vol 71 no 8 pp 4448ndash4455 2003
[20] P G Stathopoulou J C Galicia M R Benakanakere C AGarcia J Potempa and D F Kinane ldquoPorphyromonas gingi-valis induce apoptosis in human gingival epithelial cells througha gingipain-dependent mechanismrdquo BMC Microbiology vol 9article 107 2009
[21] T Murata K YaegakiW Qian et al ldquoHydrogen sulfide inducesapoptosis in epithelial cells derived from human gingivalrdquoJournal of Breath Research vol 2 no 1 Article ID 017007 2008
[22] J C Galicia M R Benakanakere P G Stathopoulou and DF Kinane ldquoNeutrophils rescue gingival epithelial cells frombacterial-induced apoptosisrdquo Journal of Leukocyte Biology vol86 no 1 pp 181ndash186 2009
[23] A Kantarci P Augustin E Firatli et al ldquoApoptosis in gingivalovergrowth tissuesrdquo Journal of Dental Research vol 86 no 9pp 888ndash892 2007
[24] VAMurrah andE PGilchrist ldquoAssessment of apoptosis in orallichen planusrdquoOral Surgery OralMedicine Oral Pathology OralRadiology and Endodontics vol 82 no 2 pp 209ndash210 1996
[25] M R Roopashree R V Gondhalekar M C Shashikanth JGeorge S H Thippeswamy and A Shukla ldquoPathogenesis oforal lichen planus a reviewrdquo Journal of Oral Pathology andMedicine vol 39 no 10 pp 729ndash734 2010
[26] R Mattila and S Syrjanen ldquoCaspase cascade pathways inapoptosis of oral lichen planusrdquo Oral Surgery Oral MedicineOral Pathology Oral Radiology and Endodontology vol 110 no5 pp 618ndash623 2010
[27] J M C Brant A C Vasconcelos and L V Rodrigues ldquoRole ofapoptosis in erosive and reticular oral lichen planus exhibiting
[28] B K Bloor F K Malik E W Odell and P R MorganldquoQuantitative assessment of apoptosis in oral lichen planusrdquoOral Surgery OralMedicine Oral Pathology Oral Radiology andEndodontics vol 88 no 2 pp 187ndash195 1999
[29] F A C G D Sousa T C Paradella Y R Carvalho and L EB Rosa ldquoImmunohistochemical expression of PCNA p53 baxand bcl-2 in oral lichen planus and epithelial dysplasiardquo Journalof oral science vol 51 no 1 pp 117ndash121 2009
[30] C Bascones-Ilundain M A Gonzalez-Moles G Esparza-Gomez J A Gil-Montoya and A Bascones-Martınez ldquoImpor-tance of apoptoticmechanisms in inflammatory infiltrate of orallichen planus lesionsrdquo Anticancer Research vol 26 no 1 pp357ndash362 2006
[31] V N Pimentel L S de Matos T C B Soares et al ldquoPerforinand granzyme B involvement in oral lesions of lichen planusand chronic GVHDrdquo Journal of Oral Pathology and Medicinevol 39 no 10 pp 741ndash746 2010
[32] L R Oliveira and S Zucoloto ldquoErythema multiforme minor arevisionrdquoTheAmerican Journal of Infectious Diseases vol 4 no4 pp 224ndash231 2008
[33] E Chrysomali F Lozada-Nur N P Dekker S I Papanicolaouand J A Regezi ldquoApoptosis in oral erythema multiformerdquo OralSurgery Oral Medicine Oral Pathology Oral Radiology andEndodontics vol 83 no 2 pp 272ndash280 1997
[34] R Abe T Shimizu A Shibaki H Nakamura HWatanabe andH Shimizu ldquoToxic epidermal necrolysis and Stevens-Johnsonsyndrome are induced by soluble fas ligandrdquo The AmericanJournal of Pathology vol 162 no 5 pp 1515ndash1520 2003
[35] S Inachi H Mizutani and M Shimizu ldquoEpidermal apop-totic cell death in erythema multiforme and Stevens-Johnsonsyndrome contribution of perforin-positive cell infiltrationrdquoArchives of Dermatology vol 133 no 7 pp 845ndash849 1997
[36] A K Vaishnaw E Toubi S Ohsako et al ldquoThe spectrumof apoptotic defects and clinical manifestations includingsystemic lupus erythematosus in humans with Cd95 (FasApo-1)mutationsrdquoArthritis and Rheumatism vol 42 no 9 pp 1833ndash1842 1999
[37] S White and A Rosen ldquoApoptosis in systemic lupus erythe-matosusrdquo Current Opinion in Rheumatology vol 15 no 5 pp557ndash562 2003
[38] D Shah S Sah and S K Nath ldquoInteraction between glu-tathione and apoptosis in systemic lupus erythematosusrdquoAutoimmunity Reviews vol 12 no 7 pp 741ndash751 2013
[39] S Rajagopalan E C Somers R D Brook et al ldquoEndothelial cellapoptosis in systemic lupus erythematosus a common pathwayfor abnormal vascular function and thrombosis propensityrdquoBlood vol 103 no 10 pp 3677ndash3683 2004
[40] M Bektas P Jolly and D S Rubenstein ldquoApoptotic pathwaysin pemphigusrdquo Dermatology Research and Practice vol 2010Article ID 456841 2010
[41] M Puviani A Marconi E Cozzani and C Pincelli ldquoFas ligandin pemphigus sera induces keratinocyte apoptosis through theactivation of caspase-8rdquo Journal of Investigative Dermatologyvol 120 no 1 pp 164ndash167 2003
[42] B H Roh K U Whang M K Cho Y L Park J S Lee andCW Lee ldquoA study of apoptosis in pemphigus vulgarisrdquo KoreanJournal of Dermatology vol 45 no 7 pp 650ndash658 2007
[43] P Deyhimi and P Tavakoli ldquoStudy of apoptosis in oral pem-phigus vulgaris using immunohistochemical marker Bax and
Journal of Oral Diseases 9
TUNEL techniquerdquo Journal of Oral Pathology andMedicine vol42 no 5 pp 409ndash414 2013
[44] B Pelacho C Natal A Espana I Sanchez-Carpintero MJ Iraburu and M J Lopez-Zabalza ldquoPemphigus vulgarisautoantibodies induce apoptosis inHaCaT keratinocytesrdquo FEBSLetters vol 566 no 1ndash3 pp 6ndash10 2004
[45] K Yoneda T Furukawa Y-J Zheng et al ldquoAn autocrineparacrine loop linking keratin 14 aggregates to tumor necrosisdactor 120572-mediated cytotoxicity in a keratinocyte model ofepidermolysis bullosa simplexrdquo Journal of Biological Chemistryvol 279 no 8 pp 7296ndash7303 2004
[46] P P Sedghizadeh C M Allen K E Anderson D H Kim JR Kalmar and J C Lang ldquoOral graft-versus-host disease andprogrammed cell death pathogenetic and clinical correlatesrdquoOral Surgery OralMedicine Oral Pathology Oral Radiology andEndodontics vol 97 no 4 pp 491ndash498 2004
[47] T A Graubert J H Russell and T J Ley ldquoThe role of granzymeB in murine models of acute graft-versus-host disease and graftrejectionrdquo Blood vol 87 no 4 pp 1232ndash1237 1996
[48] N Zavazava and D Kabelitz ldquoAlloreactivity and apoptosisin graft rejection and transplantation tolerancerdquo Journal ofLeukocyte Biology vol 68 no 2 pp 167ndash174 2000
[49] A Sarin E KHaddad and PAHenkart ldquoCaspase dependenceof target cell damage induced by cytotoxic lymphocytesrdquo Jour-nal of Immunology vol 161 no 6 pp 2810ndash2816 1998
[50] M Enari H Hug and S Nagata ldquoInvolvement of an ICE-likeprotease in Fas-mediated apoptosisrdquo Nature vol 375 no 6526pp 78ndash81 1995
[51] T H Holmstrom and J E Eriksson ldquoPhophorylation basedsignaling in Fas receptor mediated apoptosisrdquo Critical Reviewsin Immunology vol 20 pp 121ndash152 2000
[52] Y H Yoo A C Gilliam D Whitaker-Menezes R Korngoldand G F Murphy ldquoExperimental induction and ultrastructuralcharacterization of apoptosis in marine acute cutaneous graft-versus-host diseaserdquo Archives of Dermatological Research vol289 no 7 pp 389ndash398 1997
[53] Y Hayashi K Yayagi and N Haneji ldquoInvolvement of apoptoticprotease cascade for tissue destruction in Sjogrenrsquos syndromerdquoArchivum Immunologiae et Therapiae Experimentalis vol 48no 5 pp 399ndash403 2000
[54] A I Bolstad and R Jonsson ldquoThe role of apoptosis in Sjogrenrsquossyndromerdquo Annals of Internal Medicine vol 149 no 1 pp 25ndash29 1998
[55] P Manganelli and P Fietta ldquoApoptosis and Sjogren syndromerdquoSeminars in Arthritis and Rheumatism vol 33 no 1 pp 49ndash652003
[56] M Ohlsson K Skarstein A I Bolstad A C Johannessen andR Jonsson ldquoFas-induced apoptosis is a rare event in Sjogrenrsquossyndromerdquo Laboratory Investigation vol 81 no 1 pp 95ndash1052001
[57] M Sisto S Lisi D Lofrumento M DrsquoAmore P Scagliusiand VMitolo ldquoAutoantibodies from Sjogrenrsquos syndrome triggerapoptosis in salivary gland cell linerdquo Annals of the New YorkAcademy of Sciences vol 1108 pp 418ndash425 2007
[58] L S Young C W Dawson and A G Eliopoulos ldquoViruses andapoptosisrdquo British Medical Bulletin vol 53 no 3 pp 509ndash5211997
[59] B M Polster J Pevsner and J M Hardwick ldquoViral Bcl-2homologs and their role in virus replication and associateddiseasesrdquo Biochimica et Biophysica Acta vol 1644 no 2-3 pp211ndash227 2004
[60] S Cooray ldquoThe pivotal role of phosphatidylinositol 3-kinase-Akt signal transduction in virus survivalrdquo Journal of GeneralVirology vol 85 no 5 pp 1065ndash1076 2004
[61] J G Teodoro andP E Branton ldquoRegulation of apoptosis by viralgene productsrdquo Journal of Virology vol 71 no 3 pp 1739ndash17461997
[62] M L Nguyen and J A Blaho ldquoApoptosis during herpes simplexvirus infectionrdquo Advances in Virus Research vol 69 pp 67ndash972006
[63] A Kather M J Raftery G Devi-Rao et al ldquoHerpes simplexvirus type 1 (HSV-1)-induced apoptosis in human dendriticcells as a result of downregulation of cellular FLICE-inhibitoryprotein and reduced expression of HSV-1 antiapoptotic latency-associated transcript sequencesrdquo Journal of Virology vol 84 no2 pp 1034ndash1046 2010
[64] L Aurelian ldquoHSV-induced apoptosis in herpes encephalitisrdquoCurrent Topics in Microbiology and Immunology vol 289 pp79ndash111 2005
[65] J Ennaciri J Menezes F Proulx and B J Toledano ldquoInductionof apoptosis by herpes simplex virus-1 in neonatal but not adultneutrophilsrdquo Pediatric Research vol 59 no 1 pp 7ndash12 2006
[66] A M Fuentes-Gonzalez A Contreras-Paredes J Manzo-Merino and M Lizano ldquoThe modulation of apoptosis byoncogenic virusesrdquo Virology Journal vol 10 article 182 2013
[67] MThomas and L Banks ldquoInhibition of Bak-induced apoptosisby HPV-18 E6rdquo Oncogene vol 17 no 23 pp 2943ndash2954 1998
[68] M Roshal Y Zhu and V Planelles ldquoApoptosis in AIDSrdquoApoptosis vol 6 no 1-2 pp 103ndash116 2001
[69] N W Cummins and A D Badley ldquoMechanisms of HIV-associated lymphocyte apoptosis 2010rdquo Cell Death and Diseasevol 1 no 11 article e99 2010
[70] A M Loyola S V Cardoso G S Lisa et al ldquoApoptosis inepithelial cells of apical radicular cystsrdquo International Endodon-tic Journal vol 38 no 7 pp 465ndash469 2005
[71] T Suzuki H Kumamoto K Kunimori andKOoya ldquoImmuno-histochemical analysis of apoptosis-related factors in liningepithelium of radicular cystsrdquo Journal of Oral Pathology andMedicine vol 34 no 1 pp 46ndash52 2005
[72] C A Martins E R C Rivero R M Dufloth C P Figueiredoand D S C Vieira ldquoImmunohistochemical detection of factorsrelated to cellular proliferation and apoptosis in radicular anddentigerous cystsrdquo Journal of Endodontics vol 37 no 1 pp 36ndash39 2011
[73] E Kichi Y Enokiya T Muramatsu et al ldquoCell proliferationapoptosis and apoptosis-related factors in odontogenic kerato-cysts and in dentigerous cystsrdquo Journal of Oral Pathology andMedicine vol 34 no 5 pp 280ndash286 2005
[74] A Piattelli M Fioroni and C Rubini ldquoDifferentiation ofodontogenic keratocysts from other odontogenic cysts by theexpression of bcl-2 immunoreactivityrdquo Oral Oncology vol 34no 5 pp 404ndash407 1998
[75] G C P Mateus G H D S P Lanza P H R deMoura H A deMarigo and M C R Horta ldquoCell proliferation and apoptosisin keratocystic odontogenic tumorsrdquo Medicina Oral PatologiaOral y Cirugia Bucal vol 13 no 11 pp E697ndashE702 2008
[76] L Artese A Piattelli C Rubini et al ldquop16 expression inodontogenic tumorsrdquo Tumori vol 94 no 5 pp 718ndash723 2008
[77] L Lo Muzio S Staibano G Pannone et al ldquoExpression of cellcycle and apoptosis-related proteins in sporadic odontogenickeratocysts and odontogenic keratocysts associated with thenevoid basal cell carcinoma syndromerdquo Journal of DentalResearch vol 78 no 7 pp 1345ndash1353 1999
10 Journal of Oral Diseases
[78] D K Kim S G Ahn J Kim and J H Yoon ldquoComparativeKi-67 expression and apoptosis in the odontogenic keratocystassociated with or without an impacted tooth in addition tounilocular and multilocular varietiesrdquo Yonsei Medical Journalvol 44 no 5 pp 841ndash846 2003
[79] M Andric B Dozic B Popovic et al ldquoSurvivin expression inodontogenic keratocysts and correlation with cytomegalovirusinfectionrdquo Oral Diseases vol 16 no 2 pp 156ndash159 2010
[80] I R H Kramer J J Pindborg and M ShearWHOHistologicalTyping of Odontogenic Tumours Springer Berlin Germany1992
[81] H Kumamoto and K Ooya ldquoDetection of mitochondria-mediated apoptosis signaling molecules in ameloblastomasrdquoJournal of Oral Pathology and Medicine vol 34 no 9 pp 565ndash572 2005
[82] H Kumamoto and K Ooya ldquoImmunohistochemical detectionof BH3-only proteins in ameloblastic tumorsrdquo Oral Diseasesvol 14 no 6 pp 550ndash555 2008
[83] H Kumamoto and K Ooya ldquoExpression of tumor necrosisfactor120572 TNF-related apoptosis-inducing ligand and their asso-ciated molecules in ameloblastomasrdquo Journal of Oral Pathologyand Medicine vol 34 no 5 pp 287ndash294 2005
[84] H Kumamoto K Kimi and K Ooya ldquoImmunohistochemicalanalysis of apoptosis-related factors (Fas Fas ligand caspase-3and single-stranded DNA) in ameloblastomasrdquo Journal of OralPathology and Medicine vol 30 no 10 pp 596ndash602 2001
[85] T E Carneiro S A Marinho F D Verli A T M Mesquita NL Lima and J L Miranda ldquoOral squamous papilloma clinicalhistologic and immunohistochemical analysesrdquo Journal of oralscience vol 51 no 3 pp 367ndash372 2009
[86] T Yamaguchi M Shindoh A Amemiya et al ldquoDetectionof human papillomavirus type 2 related sequence in oralpapillomardquo Analytical Cellular Pathology vol 16 no 3 pp 125ndash130 1998
[87] J H Main and M Pavone ldquoActinic cheilitis and carcinoma ofthe liprdquo Journal of Canadian Dental Association vol 60 no 2pp 113ndash116 1994
[88] A Martınez U Brethauer I G Rojas et al ldquoExpression ofapoptotic and cell proliferation regulatory proteins in actiniccheilitisrdquo Journal of Oral Pathology and Medicine vol 34 no5 pp 257ndash262 2005
[89] M A Birchall C MWinterford D J Allan and B V HarmonldquoApoptosis in normal epithelium premalignant and malignantlesions of the oropharynx and oral cavity a preliminary studyrdquoEuropean Journal of Cancer B vol 31 no 6 pp 380ndash383 1995
[90] N Tanda S Mori K Saito K Ikawa and S SakamotoldquoExpression of apoptotic signaling proteins in leukoplakia andoral lichen planus quantitative and topographical studiesrdquoJournal of Oral Pathology and Medicine vol 29 no 8 pp 385ndash393 2000
[91] G Kovesi and B Szende ldquoProgression of the leukoplakia isassociated to changes in apoptotic and mitotic index as well asin p53 and Ki-67 expressionrdquo Oncology vol 46 no 4 pp 333ndash338 2002
[92] H Tsuzuki S Fujieda H Sunaga N Narita M Tokuriki andH Saito ldquoExpression of p27 and apoptosis in oral leukoplakiardquoAnticancer Research vol 23 no 2 pp 1265ndash1270 2003
[93] E Chrysomali J S Greenspan N Dekker D Greenspanand J A Regezi ldquoApoptosis-associated proteins in oral hairyleukoplakiardquo Oral Diseases vol 2 no 4 pp 279ndash284 1996
[94] S H Kaufmann andG J Gores ldquoApoptosis in cancer cause andcurerdquo BioEssays vol 22 pp 1007ndash1017 2000
[95] S Ghavami M Hashemi S R Ande et al ldquoApoptosis andcancer mutations within caspase genesrdquo Journal of MedicalGenetics vol 46 no 8 pp 497ndash510 2009
[96] C M Coutinho-Camillo S V Lourenco I N NishimotoL P Kowalski and F A Soares ldquoCaspase expression in oralsquamous cell carcinomardquo Head and Neck vol 33 no 8 pp1191ndash1198 2011
[97] P J Polverini and J E Nor ldquoApoptosis and predisposition tooral cancerrdquo Critical Reviews in Oral Biology and Medicine vol10 no 2 pp 139ndash152 1999
[98] M Sulkowska W Famulski S Sulkowski et al ldquoCorrelationbetween Bcl-2 protein expression and some clinicopathologicalfeatures of oral squamous cell carcinomardquo Polish Journal ofPathology vol 54 no 1 pp 49ndash52 2003
[99] L L Loro O K Vintermyr P G Liavaag R Jonsson and A CJohannessen ldquoOral squamous cell carcinoma is associated withdecreased bcl-2bax expression ratio and increased apoptosisrdquoHuman Pathology vol 30 no 9 pp 1097ndash1105 1999
[100] M Baltaziak M KodaM Barwijuk-Machała et al ldquoThe role ofBak expression in apoptosis of the oral squamous cell carcinoma(OSCC) and metastases to lymph nodes (LNMs)rdquo AnnalesAcademiae Medicae Bialostocensis vol 49 pp 14ndash15 2004
[101] J C de Vicente L M J Gutierrez A H Zapatero M FF Forcelledo G Hernandez-Vallejo and J S Lopez ArranzldquoPrognostic significance of p53 expression in oral squamous cellcarcinoma without neck node metastasesrdquo Head and Neck vol26 no 1 pp 22ndash30 2004
[102] M A Gonzalez-Moles P Galindo J Gutierrez-Fernandez etal ldquoP53 protein expression in oral squamous cell carcinomasurvival analysisrdquo Anticancer Research vol 21 no 4 pp 2889ndash2894 2001
[103] S Kannan G Jagadeesh Chandran K Raveendran Pillai et alldquoExpression of p53 in leukoplakia and squamous cell carcinomaof the oral mucosa correlation with expression of Ki67rdquo Journalof Clinical Pathology vol 49 no 3 pp M170ndashM175 1996
[104] J Y Koh N P Cho G Kong J D Lee and K Yoon ldquop53mutations and human papillomavirus DNA in oral squamouscell carcinoma correlation with apoptosisrdquo British Journal ofCancer vol 78 no 3 pp 354ndash359 1998
[105] L LoMuzio G Pannone S Staibano et al ldquoSurvivin expressionin oral squamous cell carcinomardquo British Journal of Cancer vol89 no 12 pp 2244ndash2248 2003
[106] Y Jinbu K Tsukinoki N Miyagi et al ldquoExpression of survivinin oral squamous cell carcinomardquo Oral Med Pathol vol 11 pp41ndash44 2006
[107] C Jane A V Nerurkar N V Shirsat R B DeshpandeA D Amrapurkar and F R Karjodkar ldquoIncreased survivinexpression in high-grade oral squamous cell carcinoma a studyin Indian tobacco chewersrdquo Journal of Oral Pathology andMedicine vol 35 no 10 pp 595ndash601 2006
[108] Y-H Kim S-M Kim Y-K Kim S-P Hong M-J Kim andH Myoung ldquoEvaluation of survivin as a prognostic marker inoral squamous cell carcinomardquo Journal of Oral Pathology andMedicine vol 39 no 5 pp 368ndash375 2010
[109] N G Nikitakis J J Sauk and S I Papanicolaou ldquoThe role ofapoptosis in oral disease mechanisms aberrations in neoplas-tic autoimmune infectious hematologic and developmentaldiseases and therapeutic opportunitiesrdquo Oral Surgery OralMedicine Oral Pathology Oral Radiology and Endodontics vol97 no 4 pp 476ndash490 2004
[110] L L Loro O K Vintermyr A C Johannessen P G Liavaagand R Jonsson ldquoSuppression of Fas receptor and negative
Journal of Oral Diseases 11
correlation of Fas ligand with differentiation and apoptosis inoral squamous cell carcinomardquo Journal of Oral Pathology andMedicine vol 28 no 2 pp 82ndash87 1999
[111] N H Al-Rawi H Omer and S Al Kawas ldquoImmunohistochem-ical analysis of P53 and bcl-2 in benign and malignant salivaryglands tumorsrdquo Journal of Oral Pathology and Medicine vol 39no 1 pp 48ndash55 2010
[112] ANordkvist E Roijer G Bang et al ldquoExpression andmutationpatterns of p53 in benign andmalignant salivary gland tumorsrdquoInternational Journal of Oncology vol 16 no 3 pp 477ndash4832000
[113] V J Karja K J Syrjanen A-K Kurvinen and S M SyrjanenldquoExpression and mutations of p53 in salivary gland tumoursrdquoJournal of Oral Pathology and Medicine vol 26 no 5 pp 217ndash223 1997
[114] M Yanezez I Roa M Garcıa G Ibacache and M VillasecaldquoGene Bcl-2 protein expression in salivary gland tumorsrdquoRevista Medica de Chile vol 127 no 2 pp 139ndash142 1999
[115] L Jia R L Esguerra X Tang et al ldquoPrognostic value ofapoptosis and apoptosis-associated proteins in salivary glandadenoid cystic carcinomardquo Pathology International vol 54 no4 pp 217ndash223 2004
[116] Y Soini U Tormanen and P Paakko ldquoApoptosis is inverselyrelated to bcl-2 but not to bax expression in salivary glandtumoursrdquo Histopathology vol 32 no 1 pp 28ndash34 1998
[117] R M Nagler H Kerner S Ben-Eliezer I Minkov and O Ben-Itzhak ldquoPrognostic role of apoptotic Bcl-2 c-erbB-2 and p53tumor markers in salivary gland malignanciesrdquo Oncology vol64 no 4 pp 389ndash398 2003
apoptotic cell death from ensuingThis apoptoticmodulationhas a role in the development of herpetic disease [62] HSV-1-induced apoptosis of immature dendritic cells is associatedwith downregulation of the cellular FLICE-inhibitory protein(c-FLIP) in a proteasome-independent manner [63] HSV-1triggers apoptosis in CNS neurons and causes encephalitis inadult subjects [64] HSV-1 enhances apoptosis via expressionof both Fas and Fas ligand on the surface of neonatalneutrophils [65]
High risk HPV oncoproteins E6 E7 and E5 can mod-ulate host mediated apoptosis by inhibiting death receptorsignaling and thus regulate the survival of infected cells [66]HPV E6 proteins inhibit apoptosis in both p53-dependentand p53-independent manners HPV-18 E6 inhibits Bak-induced apoptosis in differentiating keratinocytes in whichHPV replicates It was also suggested that Bak is probably thefirst naturally occurring target of ubiquitin ligase E6AP [67]
HIV infection usually leads to progressive immunod-eficiency and loss of immune competence associated withdeclines in both the functionality and the number of CD4+lymphocytes which in turn is related to various viral andimmunological processes Proposed virus-mediated mech-anisms include toxicity caused by accumulation of uninte-grated viral DNA alteration in membrane permeability dueto budding of viral particles and terminal differentiationAmong the immunological mechanisms are killing by spe-cific CTL and signaling through the CD4 molecule leadingto CD4+ lymphocytes apoptosis [68] Apoptosis in HIV maybe stimulated by environmental stress toxins and removalof growth factors and may be mediated by one of thesedeath inducing ligands TNF FasL and TRAIL [69] Manyof the proteins that are encoded by the HIV genome havebeen found to have pro- andor antiapoptotic qualities HIVsurface glycoprotein gp120 cross-links CD4 and primes cellsfor apoptosis HIV-1 can also induce apoptosis ldquofrom withinrdquovia expression of certain viral genes such as tat nef vpu andvpr [68 69]
35 Apoptosis and Benign Entities
351 Apoptosis and Benign Odontogenic Cysts and Tumors
(1) Apoptosis and RadicularApical Cyst Radicular cysts arethe most common cystic lesions of the jaws and representa periapical inflammatory disease evoked by infected andnecrotic dental pulp Apoptosis was found to be alwayspresent in the epithelium of the apical radicular cyst Higherapoptotic index (AI) and bcl-2 index (bcl-2I) were found inlesions with atrophic compared to hyperplastic epitheliumbut the difference was statistically insignificant However apositive and significant correlation was found between AIand bcl-2I [70] Epithelium of radicular and residual cystsshowed expression of apoptosis related factors like ssDNAp53 Bax Bcl-2 caspase-3 Fas Fas-L and Ki-67 antigensuggesting their role in the pathophysiologic activity ofperiapical inflammatory lesions Such factors may be affectedby the structure of lining epithelium and the degree ofinflammatory change since Ki-67 and ssDNA reactivity inRCs with intense inflammatory reactions or with thick lining
epithelium were significantly stronger than those RCs withless inflammation or with thin lining [71] Caspase-3 andKi-67 expression was significant in hyperplastic epitheliumrelated to intense inflammation whereas Bcl-2 expressionwas significantly higher in atrophic epithelium of DCs thanRCs suggesting that although they may have different patho-genetic mechanism they have similar biological behavior inthe presence of intense inflammatory infiltrate [72]
(2) Apoptosis and Dentigerous Cyst The epithelial lining ofDCs has shown TUNEL Ki-67 and p53 positivity but theexpression was weak as compared to OKCs indicating thatapoptosis is involved in cyst formation and maintainingthe regular thickness of the lining epithelium in DCs [73]Bcl-2 positivity was significantly higher in atrophic epithe-lium of DCs than that of RCs suggesting that presence ofinflammation inhibits the Bcl-2 expression and both cystshave similar biological behavior in the presence of intenseinflammatory infiltrate [72] whereas other demonstrated thatBcl-2 expression was almost completely negative in DCs andRCs compared to OKCs [74]
(3) Apoptosis and Odontogenic KeratocystKeratocystic Odon-togenic Tumor Keratocystic odontogenic tumor (KCOT)also known as odontogenic keratocyst (OKC) was recentlyclassified as a benign neoplasia due to the aggressive clinicalbehavior The proliferation index and apoptotic index werefound to be higher and with distinct pattern in both sporadicand nevoid basal cell carcinoma syndrome (NBCCS) KCOTscompared to DCs reflecting its high cell turnover andreinforcing its classification as an odontogenic tumor [75]Lack of p16 expression in KCOT compared to strong ormoderate p16 expression in RCs and follicular cysts couldbe related to the increased aggressive behavior invasivenessand high frequency of recurrences found in KCOT [76]Overexpression of cyclin Dl and p53 in syndromic OKCscould be considered as hallmark of a mutated cellular phe-notype and more aggressive clinical behaviour compared tosporadic KCOTs which were negative for these oncoproteins[77] Strong Bcl-2 overexpression in OKCs suggests its rolein extension of cell survival leading to the peculiar aggressivegrowth pattern and can be useful to differentiate OKC fromother odontogenic cysts [74] TUNEL positive cells wereobserved in the surface layers of OKCs whereas no positivitywas seen in the basal or intermediate layers of OKCs andDCs Also Ki67-positive ratio and p53-positive ratio in theintermediate layer were the highest in OKCs and Bcl-2-positive cells were discernible exclusively in the basal layerof OKCs signifying that subsequently OKCs are seen ascystic lesions but not as tumor masses [73] There is nosignificant difference in proliferative activity and apoptosisin OKCs associated with or without impacted teeth orbetween the unilocular ormultilocular variants [78] Survivinimmunoexpression was positive in all cases of OKCs while allperiapical cysts were negative suggesting its contribution toviolent behavior of OKCs [79]
(4) Apoptosis and Ameloblastomas Ameloblastoma isthe most frequently encountered tumor arising from
6 Journal of Oral Diseases
odontogenic epithelium and is characterized by a benign butlocally invasive behavior with a high risk of recurrence [80]
RT-PCR and IHC showed expression of cytochrome cAPAF-1 caspase-9 and AIF in tooth germs and benign andmalignant ameloblastomas suggesting that themitochondria-mediated apoptotic pathway has a role in apoptotic celldeath of normal and neoplastic odontogenic epithelium andmight be involved in oncogenesis cytodifferentiation andmalignant transformation of odontogenic epithelium [81]
Granular cells basal cells desmoplastic ameloblastomasand ameloblastic carcinomas showed immunoreactivity forthe BH3-only proteins (Bid Bim Bad Noxa and Puma)whereas keratinising cells of acanthomatous ameloblastomasshowed no reactivity suggesting that these proteins mightbe involved in tumor cell differentiation of ameloblastomas[82] TNF-120572 TRAIL and their receptors were also found tobe expressed in tooth germs and ameloblastomas provingtheir role in cytodifferentiation of odontogenic epitheliumand tissue structuring of ameloblastomas [83] Similarlyexpression of Fas FasL caspase-3 and ssDNA has also beendemonstrated in various patterns in tooth germs and benignand malignant ameloblastomas [84]
352 Apoptosis and Benign Epithelial Tumor
(1) Apoptosis and Squamous PapillomaOral squamous papil-loma (OSP) is a frequent benign tumorous lesion associatedwith HPV OSP consists of proliferation of the stratifiedsquamous epithelium resulting in a papillary or verrucousexophytic mass and has got site predilection for the tongueand soft palate but any surface of the oral cavity can beaffected [85 86] Carneiro et al performed immunohisto-chemical assay on 12 OSP cases utilizing BP53-12 and Pab240antibodies for p53 protein and found that immunostainingfor protein p53 was primarily negative or weakly positivein all cases (in all epithelial layers) except one case whichindicates the benign nature of the lesions evidenced by theirslow development and less chances of becoming malignantIntense staining in one slide for both immunomarkers in allthe epithelial layers could be attributed to the presence ofvirus with high oncogenic potential (HPV 16 and 18) or tothe presence of coexisting external factors [85]
36 Apoptosis and Premalignant and Malignant Entities
361 Apoptosis and Actinic Cheilitis Actinic cheilitis (AC) isa common condition caused by damage to the lips throughexposure to sunlight and has the potential to undergomalignant transformation into squamous cell carcinoma [87]Overexpression of p53 was found in AC as compared tonormal lip and oral mucosa Bcl-2 expression was higherin AC than in oral mucosa but it was significantly reducedas compared with normal lip Thus it was suggested thatDNA-damaged cells by UV radiation in AC are eliminatedby apoptosis Also both p53 and bcl-2 play an important rolein regulating malignant transformation in AC [88]
362 Apoptosis and Oral Leukoplakia It has been sug-gested that a change in apoptosis accompanies the onset
of invasion in a premalignant lesion of the human oralcavity and oropharynx AI increased progressively fromnormal to carcinoma in situ (CIS) but fell in SCC withmaximum apoptotic index (AI) mitotic index (MI) ratioin CIS The position of apoptotic bodies was localised tothe deepest layers in normal and dysplastic epithelia butbecame generalised in CIS and SCC [89] Greater expressionof oncoproteins MDM2 and Bcl-2 was seen in leukoplakiawith altered keratinocyte maturation than OLP case whereasexpression of wt-p53 and p21 was higher in OLP compared toleukoplakia cases In spite of divergent outcome of apoptoticsignalling proteins no significant difference in the number ofapoptotic epithelial cells was observed between leukoplakiaand OLP cases [90] Increased mitotic apoptotic and Ki-67 index indicate unfavourable prognosis of leukoplakia [91]Abundance of p27 expression in oral leukoplakia may beassociated with inhibition of cell proliferation leading toapoptosis of premalignant tumor cells thus preventing tumorprogression [92] It is hypothesised that the antiapoptoticability of Epstein-Barr virus (EBV) may result in alteredexpression of apoptosis-associated proteins in oral hairyleukoplakia Except p53 which appears to be overexpressedthere is only slight alteration in immunoexpression of otherapoptosis-associated proteins in OHL [93]
363 Apoptosis and Oral Squamous Cell Carcinoma Theaccumulation of neoplastic cells can occur through enhancedproliferation diminished cell turnover or a combination ofboth processes Tumor cells from a wide variety of humancancers have been shown to exhibit increased survival andresistance to apoptosis [94] There are two major ways thatcould downregulate cancer cell apoptosis (1) somatic andnonsomatic mutation and loss of expression of proapoptoticmolecules and (2) overexpression of apoptosis inhibitorymolecules Mutations within caspase family proteases are notuncommon in malignancies [95] Caspase-7 proved to bean independent prognosticator and predictor of locoregionalrecurrence in patients of OSCC [96] Several alterations thatinhibit both the death receptor and mitochondrial pathwaysvia caspases have also been identified including overexpres-sion of IAPs activation of PI3k or Akt and posttranslationalmodifications of caspases [94]
In pathological settings Bcl-2 gene family appears toact synergistically with oncogenes and tumor suppressorgenes [97] Positive Bcl-2 expression is associated with highertumor grading higher tumor mitotic index higher index ofatypical mitoses and microfocal pattern of tumor invasivemargins [98] In OSCC compared with oral epitheliumthere is a decreased Bcl-2 expression a lowered Bcl-2Baxratio and increased apoptosis Expression of Bax correlatedwith histological tumor grading in OSCC [99] whereasothers found that expression of Bak may be useful for bettercharacterizing and predicting the prognosis of OSCC [100]
Aberrations of the p53 gene and overexpression of its pro-tein are widely recognized markers of malignancy includingOSCC It was found that there is a negative correlation of p53immunoexpression with histologic grade of differentiationIn patients without neck node metastases p53 showed astrong correlation with survival [101] On the contrary
Journal of Oral Diseases 7
another study showed that expression of p53 protein did notbehave as amarker of prognostic value in patients withOSCC[102]
As cancer is characterized by uncontrolled cell prolif-eration markers of proliferation such as Ki67 and PCNAhave been studied extensively in neoplastic lesions Expres-sion of both p53 and Ki67 correlated significantly with thehistopathological stage of the tumor However expression ofp53 was not correlated with that of Ki67 [103]
HPV infection andor p53 mutations are implicated incarcinogenesis of oral SCC but are not mutually exclusiveevents Moreover decrease in apoptosis is more closelyrelated to p53 mutation than HPV infection [104]
Survivin has got a versatile role in modulating celldivision and apoptosis in cancer Low survivin expressioncorrelated statistically significantly with better survival ratesbut not with age sex tumor size the presence of lymphnode or distant metastases [105] Survivin was found tobe preferentially expressed in nonadvanced nonmetastaticand chemotherapy-sensitive OSCC [106] On the contraryincreased expression of survivin was found in high-gradetumors suggesting its contribution to apoptosis resistancein response to therapy [107] Also significant correlationbetween survivin expression lymph node metastasis andproliferation was revealed but not with differentiationmicrovessel density or TNM staging [108]
Upregulation of FasL and downregulation of Fas havebeen shown to occur in oral carcinogenesis possibly con-tributing to both cancer cell survival and evasion of the hostimmune assault through induction of apoptosis in T cellsthat would normally kill tumor cells [109] Moreover it hasbeen found that Fas is expressed in low quantities in OSCCwhereas FasL expression correlates negatively with degree ofdifferentiation and apoptosis in OSCC [110] Thus variousproteins (apoptotic and antiapoptotic) have got a significantbearing in initiation progression and prognosis of OSCC
37 Apoptosis and Salivary Gland Tumors Salivary glandtumors (SGT) are relatively uncommon neoplasms withwidely variable histopathologic and biologic characteristicsP53bcl-2 immunostaining reactivity could be helpful indemonstrating SGT behavior in terms of progression andextent of invasion since all malignant salivary gland tumorswere positive whereas 70 of pleomorphic adenomas (PA)showed negative expression [111] Similarly Nordkvist et alfound p53 overexpression in 20 of the malignant SGT withthe highest prevalence in PLGA squamous cell carcinomaand CaXPA and the lowest in adenoid cystic carcinomaand acinic cell carcinoma but none of the benign PA [112]Expression of p53 in malignant tumors bore no correlationto local recurrence metastatic disease or survival of thepatients [113] Bcl-2 protein expression was found virtuallyin all benign and malignant SGT suggesting its role in thedevelopment and proliferation of these tumors via inhibitionof apoptosis [114] p53 expression apoptotic index and bcl-2 protein are potential prognostic parameters in salivarygland adenoid cystic carcinoma [115] Frequency of apoptosisis inversely related to bcl-2 but not to Bax expression inSGT [116] Survival probability of patients who demonstrated
positive staining for c-erbB-2 or TUNEL or both was lowerthan those with negative staining [117]
4 Conclusion
Understanding the mechanistic machinery of apoptosis iscrucial because it influences both health and disease beinginitiated by various physiologic and pathologic stimuliMore-over the extensive involvement of apoptosis in the patho-genesis of various oral diseases and meticulous knowledgeabout it prompt it to therapeutic intervention at differentcheckpoints This review is an attempt to provide an updateon the crucial role and importance of apoptosis in various oralpathologies
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] A Lawen ldquoApoptosis an introductionrdquo BioEssays vol 25 no 9pp 888ndash896 2003
[2] J F Kerr A H Wyllie and A R Currie ldquoApoptosis abasic biological phenomenon with wide-ranging implicationsin tissue kineticsrdquo British Journal of Cancer vol 26 no 4 pp239ndash257 1972
[3] A Strasser L OrsquoConnor and V M Dixit ldquoApoptosis signalingrdquoAnnual Review of Biochemistry vol 69 pp 217ndash245 2000
[4] N Singh ldquoApoptosis in health and disease and modulation ofapoptosis for therapy an overviewrdquo Indian Journal of ClinicalBiochemistry vol 22 no 2 pp 6ndash16 2007
[5] T-J Fan L-H Han R-S Cong and J Liang ldquoCaspase familyproteases and apoptosisrdquo Acta Biochimica et Biophysica Sinicavol 37 no 11 pp 719ndash727 2005
[6] P C Ashe and M D Berry ldquoApoptotic signaling cascadesrdquoProgress in Neuro-Psychopharmacology and Biological Psychia-try vol 27 no 2 pp 199ndash214 2003
[7] L L Loro O K Vintermyr and A C Johannessen ldquoApoptosisin normal and diseased oral tissuesrdquoOral Diseases vol 11 no 5pp 274ndash287 2005
[8] H Jafarzadeh M Sanatkhani and N Mohtasham ldquoOral pyo-genic granuloma a reviewrdquo Journal of Oral Science vol 48 no4 pp 167ndash175 2006
[9] T Nakamura ldquoApoptosis and expression of BaxBcl-2 proteinsin pyogenic granuloma a comparative study with granulationtissue and capillary hemangiomardquo Journal of Cutaneous Pathol-ogy vol 27 no 8 pp 400ndash405 2000
[10] K Yuan L-Y C Wing and M T Lin ldquoPathogenetic roles ofangiogenic factors in pyogenic granulomas in pregnancy aremodulated by female sex hormonesrdquo Journal of Periodontologyvol 73 no 7 pp 701ndash708 2002
[11] K Yuan and M T Lin ldquoThe roles of vascular endothelialgrowth factor and angiopoietin-2 in the regression of pregnancypyogenic granulomardquo Oral Diseases vol 10 no 3 pp 179ndash1852004
[12] F R Amaral V F Bernardes A P Duarte et al ldquoQuantitativeexpression analysis of apoptoticantiapoptotic genes and associ-ationwith immunolocalization of BAX andBCL-2 in peripheral
8 Journal of Oral Diseases
and central giant cell lesions of the jawsrdquo Tumor Biology vol 32no 5 pp 997ndash1003 2011
[13] J Pammer W Weninger H Hulla P Mazal and R HorvatldquoExpression of regulatory apoptotic proteins in peripheral giantcell granulomas and lesions containing osteoclast-like giantcellsrdquo Journal of Oral Pathology and Medicine vol 27 no 6 pp267ndash271 1998
[14] C Scully and S Porter ldquoOral mucosal disease recurrentaphthous stomatitisrdquo British Journal of Oral and MaxillofacialSurgery vol 46 no 3 pp 198ndash206 2008
[15] T Honma T Saito and Y Fujioka ldquoPossible role of apoptoticcells of the oral epithelium in the pathogenesis of aphthousulcerationrdquoOral Surgery Oral Medicine and Oral Pathology vol59 no 4 pp 379ndash387 1985
[16] J F N Pinto Rodrigues C T Fujiyama Oshima A P RibeiroPaiotti M Franco S S Miki Ihara and D A RibeiroldquoExpression of apoptosis regulatory proteins p53 bcl-2 andbax in recurrent aphthous ulcerationrdquo Journal of the EuropeanAcademy of Dermatology and Venereology vol 26 no 10 pp1247ndash1251 2012
[17] J Gamonal A Bascones A Acevedo E Blanco and A SilvaldquoApoptosis in chronic adult periodontitis analyzed by in situDNA breaks electron microscopy and immunohistochem-istryrdquo Journal of Periodontology vol 72 no 4 pp 517ndash525 2001
[18] F Jarnbring E Somogyi J Dalton A Gustafsson and BKlinge ldquoQuantitative assessment of apoptotic and prolifera-tive gingival keratinocytes in oral and sulcular epithelium inpatients with gingivitis and periodontitisrdquo Journal of ClinicalPeriodontology vol 29 no 12 pp 1065ndash1071 2002
[19] P Kelk A Johansson R Claesson L Hanstrom and S KalfasldquoCaspase 1 involvement in human monocyte lysis induced byActinobacillus actinomycetemcomitans leukotoxinrdquo Infectionand Immunity vol 71 no 8 pp 4448ndash4455 2003
[20] P G Stathopoulou J C Galicia M R Benakanakere C AGarcia J Potempa and D F Kinane ldquoPorphyromonas gingi-valis induce apoptosis in human gingival epithelial cells througha gingipain-dependent mechanismrdquo BMC Microbiology vol 9article 107 2009
[21] T Murata K YaegakiW Qian et al ldquoHydrogen sulfide inducesapoptosis in epithelial cells derived from human gingivalrdquoJournal of Breath Research vol 2 no 1 Article ID 017007 2008
[22] J C Galicia M R Benakanakere P G Stathopoulou and DF Kinane ldquoNeutrophils rescue gingival epithelial cells frombacterial-induced apoptosisrdquo Journal of Leukocyte Biology vol86 no 1 pp 181ndash186 2009
[23] A Kantarci P Augustin E Firatli et al ldquoApoptosis in gingivalovergrowth tissuesrdquo Journal of Dental Research vol 86 no 9pp 888ndash892 2007
[24] VAMurrah andE PGilchrist ldquoAssessment of apoptosis in orallichen planusrdquoOral Surgery OralMedicine Oral Pathology OralRadiology and Endodontics vol 82 no 2 pp 209ndash210 1996
[25] M R Roopashree R V Gondhalekar M C Shashikanth JGeorge S H Thippeswamy and A Shukla ldquoPathogenesis oforal lichen planus a reviewrdquo Journal of Oral Pathology andMedicine vol 39 no 10 pp 729ndash734 2010
[26] R Mattila and S Syrjanen ldquoCaspase cascade pathways inapoptosis of oral lichen planusrdquo Oral Surgery Oral MedicineOral Pathology Oral Radiology and Endodontology vol 110 no5 pp 618ndash623 2010
[27] J M C Brant A C Vasconcelos and L V Rodrigues ldquoRole ofapoptosis in erosive and reticular oral lichen planus exhibiting
[28] B K Bloor F K Malik E W Odell and P R MorganldquoQuantitative assessment of apoptosis in oral lichen planusrdquoOral Surgery OralMedicine Oral Pathology Oral Radiology andEndodontics vol 88 no 2 pp 187ndash195 1999
[29] F A C G D Sousa T C Paradella Y R Carvalho and L EB Rosa ldquoImmunohistochemical expression of PCNA p53 baxand bcl-2 in oral lichen planus and epithelial dysplasiardquo Journalof oral science vol 51 no 1 pp 117ndash121 2009
[30] C Bascones-Ilundain M A Gonzalez-Moles G Esparza-Gomez J A Gil-Montoya and A Bascones-Martınez ldquoImpor-tance of apoptoticmechanisms in inflammatory infiltrate of orallichen planus lesionsrdquo Anticancer Research vol 26 no 1 pp357ndash362 2006
[31] V N Pimentel L S de Matos T C B Soares et al ldquoPerforinand granzyme B involvement in oral lesions of lichen planusand chronic GVHDrdquo Journal of Oral Pathology and Medicinevol 39 no 10 pp 741ndash746 2010
[32] L R Oliveira and S Zucoloto ldquoErythema multiforme minor arevisionrdquoTheAmerican Journal of Infectious Diseases vol 4 no4 pp 224ndash231 2008
[33] E Chrysomali F Lozada-Nur N P Dekker S I Papanicolaouand J A Regezi ldquoApoptosis in oral erythema multiformerdquo OralSurgery Oral Medicine Oral Pathology Oral Radiology andEndodontics vol 83 no 2 pp 272ndash280 1997
[34] R Abe T Shimizu A Shibaki H Nakamura HWatanabe andH Shimizu ldquoToxic epidermal necrolysis and Stevens-Johnsonsyndrome are induced by soluble fas ligandrdquo The AmericanJournal of Pathology vol 162 no 5 pp 1515ndash1520 2003
[35] S Inachi H Mizutani and M Shimizu ldquoEpidermal apop-totic cell death in erythema multiforme and Stevens-Johnsonsyndrome contribution of perforin-positive cell infiltrationrdquoArchives of Dermatology vol 133 no 7 pp 845ndash849 1997
[36] A K Vaishnaw E Toubi S Ohsako et al ldquoThe spectrumof apoptotic defects and clinical manifestations includingsystemic lupus erythematosus in humans with Cd95 (FasApo-1)mutationsrdquoArthritis and Rheumatism vol 42 no 9 pp 1833ndash1842 1999
[37] S White and A Rosen ldquoApoptosis in systemic lupus erythe-matosusrdquo Current Opinion in Rheumatology vol 15 no 5 pp557ndash562 2003
[38] D Shah S Sah and S K Nath ldquoInteraction between glu-tathione and apoptosis in systemic lupus erythematosusrdquoAutoimmunity Reviews vol 12 no 7 pp 741ndash751 2013
[39] S Rajagopalan E C Somers R D Brook et al ldquoEndothelial cellapoptosis in systemic lupus erythematosus a common pathwayfor abnormal vascular function and thrombosis propensityrdquoBlood vol 103 no 10 pp 3677ndash3683 2004
[40] M Bektas P Jolly and D S Rubenstein ldquoApoptotic pathwaysin pemphigusrdquo Dermatology Research and Practice vol 2010Article ID 456841 2010
[41] M Puviani A Marconi E Cozzani and C Pincelli ldquoFas ligandin pemphigus sera induces keratinocyte apoptosis through theactivation of caspase-8rdquo Journal of Investigative Dermatologyvol 120 no 1 pp 164ndash167 2003
[42] B H Roh K U Whang M K Cho Y L Park J S Lee andCW Lee ldquoA study of apoptosis in pemphigus vulgarisrdquo KoreanJournal of Dermatology vol 45 no 7 pp 650ndash658 2007
[43] P Deyhimi and P Tavakoli ldquoStudy of apoptosis in oral pem-phigus vulgaris using immunohistochemical marker Bax and
Journal of Oral Diseases 9
TUNEL techniquerdquo Journal of Oral Pathology andMedicine vol42 no 5 pp 409ndash414 2013
[44] B Pelacho C Natal A Espana I Sanchez-Carpintero MJ Iraburu and M J Lopez-Zabalza ldquoPemphigus vulgarisautoantibodies induce apoptosis inHaCaT keratinocytesrdquo FEBSLetters vol 566 no 1ndash3 pp 6ndash10 2004
[45] K Yoneda T Furukawa Y-J Zheng et al ldquoAn autocrineparacrine loop linking keratin 14 aggregates to tumor necrosisdactor 120572-mediated cytotoxicity in a keratinocyte model ofepidermolysis bullosa simplexrdquo Journal of Biological Chemistryvol 279 no 8 pp 7296ndash7303 2004
[46] P P Sedghizadeh C M Allen K E Anderson D H Kim JR Kalmar and J C Lang ldquoOral graft-versus-host disease andprogrammed cell death pathogenetic and clinical correlatesrdquoOral Surgery OralMedicine Oral Pathology Oral Radiology andEndodontics vol 97 no 4 pp 491ndash498 2004
[47] T A Graubert J H Russell and T J Ley ldquoThe role of granzymeB in murine models of acute graft-versus-host disease and graftrejectionrdquo Blood vol 87 no 4 pp 1232ndash1237 1996
[48] N Zavazava and D Kabelitz ldquoAlloreactivity and apoptosisin graft rejection and transplantation tolerancerdquo Journal ofLeukocyte Biology vol 68 no 2 pp 167ndash174 2000
[49] A Sarin E KHaddad and PAHenkart ldquoCaspase dependenceof target cell damage induced by cytotoxic lymphocytesrdquo Jour-nal of Immunology vol 161 no 6 pp 2810ndash2816 1998
[50] M Enari H Hug and S Nagata ldquoInvolvement of an ICE-likeprotease in Fas-mediated apoptosisrdquo Nature vol 375 no 6526pp 78ndash81 1995
[51] T H Holmstrom and J E Eriksson ldquoPhophorylation basedsignaling in Fas receptor mediated apoptosisrdquo Critical Reviewsin Immunology vol 20 pp 121ndash152 2000
[52] Y H Yoo A C Gilliam D Whitaker-Menezes R Korngoldand G F Murphy ldquoExperimental induction and ultrastructuralcharacterization of apoptosis in marine acute cutaneous graft-versus-host diseaserdquo Archives of Dermatological Research vol289 no 7 pp 389ndash398 1997
[53] Y Hayashi K Yayagi and N Haneji ldquoInvolvement of apoptoticprotease cascade for tissue destruction in Sjogrenrsquos syndromerdquoArchivum Immunologiae et Therapiae Experimentalis vol 48no 5 pp 399ndash403 2000
[54] A I Bolstad and R Jonsson ldquoThe role of apoptosis in Sjogrenrsquossyndromerdquo Annals of Internal Medicine vol 149 no 1 pp 25ndash29 1998
[55] P Manganelli and P Fietta ldquoApoptosis and Sjogren syndromerdquoSeminars in Arthritis and Rheumatism vol 33 no 1 pp 49ndash652003
[56] M Ohlsson K Skarstein A I Bolstad A C Johannessen andR Jonsson ldquoFas-induced apoptosis is a rare event in Sjogrenrsquossyndromerdquo Laboratory Investigation vol 81 no 1 pp 95ndash1052001
[57] M Sisto S Lisi D Lofrumento M DrsquoAmore P Scagliusiand VMitolo ldquoAutoantibodies from Sjogrenrsquos syndrome triggerapoptosis in salivary gland cell linerdquo Annals of the New YorkAcademy of Sciences vol 1108 pp 418ndash425 2007
[58] L S Young C W Dawson and A G Eliopoulos ldquoViruses andapoptosisrdquo British Medical Bulletin vol 53 no 3 pp 509ndash5211997
[59] B M Polster J Pevsner and J M Hardwick ldquoViral Bcl-2homologs and their role in virus replication and associateddiseasesrdquo Biochimica et Biophysica Acta vol 1644 no 2-3 pp211ndash227 2004
[60] S Cooray ldquoThe pivotal role of phosphatidylinositol 3-kinase-Akt signal transduction in virus survivalrdquo Journal of GeneralVirology vol 85 no 5 pp 1065ndash1076 2004
[61] J G Teodoro andP E Branton ldquoRegulation of apoptosis by viralgene productsrdquo Journal of Virology vol 71 no 3 pp 1739ndash17461997
[62] M L Nguyen and J A Blaho ldquoApoptosis during herpes simplexvirus infectionrdquo Advances in Virus Research vol 69 pp 67ndash972006
[63] A Kather M J Raftery G Devi-Rao et al ldquoHerpes simplexvirus type 1 (HSV-1)-induced apoptosis in human dendriticcells as a result of downregulation of cellular FLICE-inhibitoryprotein and reduced expression of HSV-1 antiapoptotic latency-associated transcript sequencesrdquo Journal of Virology vol 84 no2 pp 1034ndash1046 2010
[64] L Aurelian ldquoHSV-induced apoptosis in herpes encephalitisrdquoCurrent Topics in Microbiology and Immunology vol 289 pp79ndash111 2005
[65] J Ennaciri J Menezes F Proulx and B J Toledano ldquoInductionof apoptosis by herpes simplex virus-1 in neonatal but not adultneutrophilsrdquo Pediatric Research vol 59 no 1 pp 7ndash12 2006
[66] A M Fuentes-Gonzalez A Contreras-Paredes J Manzo-Merino and M Lizano ldquoThe modulation of apoptosis byoncogenic virusesrdquo Virology Journal vol 10 article 182 2013
[67] MThomas and L Banks ldquoInhibition of Bak-induced apoptosisby HPV-18 E6rdquo Oncogene vol 17 no 23 pp 2943ndash2954 1998
[68] M Roshal Y Zhu and V Planelles ldquoApoptosis in AIDSrdquoApoptosis vol 6 no 1-2 pp 103ndash116 2001
[69] N W Cummins and A D Badley ldquoMechanisms of HIV-associated lymphocyte apoptosis 2010rdquo Cell Death and Diseasevol 1 no 11 article e99 2010
[70] A M Loyola S V Cardoso G S Lisa et al ldquoApoptosis inepithelial cells of apical radicular cystsrdquo International Endodon-tic Journal vol 38 no 7 pp 465ndash469 2005
[71] T Suzuki H Kumamoto K Kunimori andKOoya ldquoImmuno-histochemical analysis of apoptosis-related factors in liningepithelium of radicular cystsrdquo Journal of Oral Pathology andMedicine vol 34 no 1 pp 46ndash52 2005
[72] C A Martins E R C Rivero R M Dufloth C P Figueiredoand D S C Vieira ldquoImmunohistochemical detection of factorsrelated to cellular proliferation and apoptosis in radicular anddentigerous cystsrdquo Journal of Endodontics vol 37 no 1 pp 36ndash39 2011
[73] E Kichi Y Enokiya T Muramatsu et al ldquoCell proliferationapoptosis and apoptosis-related factors in odontogenic kerato-cysts and in dentigerous cystsrdquo Journal of Oral Pathology andMedicine vol 34 no 5 pp 280ndash286 2005
[74] A Piattelli M Fioroni and C Rubini ldquoDifferentiation ofodontogenic keratocysts from other odontogenic cysts by theexpression of bcl-2 immunoreactivityrdquo Oral Oncology vol 34no 5 pp 404ndash407 1998
[75] G C P Mateus G H D S P Lanza P H R deMoura H A deMarigo and M C R Horta ldquoCell proliferation and apoptosisin keratocystic odontogenic tumorsrdquo Medicina Oral PatologiaOral y Cirugia Bucal vol 13 no 11 pp E697ndashE702 2008
[76] L Artese A Piattelli C Rubini et al ldquop16 expression inodontogenic tumorsrdquo Tumori vol 94 no 5 pp 718ndash723 2008
[77] L Lo Muzio S Staibano G Pannone et al ldquoExpression of cellcycle and apoptosis-related proteins in sporadic odontogenickeratocysts and odontogenic keratocysts associated with thenevoid basal cell carcinoma syndromerdquo Journal of DentalResearch vol 78 no 7 pp 1345ndash1353 1999
10 Journal of Oral Diseases
[78] D K Kim S G Ahn J Kim and J H Yoon ldquoComparativeKi-67 expression and apoptosis in the odontogenic keratocystassociated with or without an impacted tooth in addition tounilocular and multilocular varietiesrdquo Yonsei Medical Journalvol 44 no 5 pp 841ndash846 2003
[79] M Andric B Dozic B Popovic et al ldquoSurvivin expression inodontogenic keratocysts and correlation with cytomegalovirusinfectionrdquo Oral Diseases vol 16 no 2 pp 156ndash159 2010
[80] I R H Kramer J J Pindborg and M ShearWHOHistologicalTyping of Odontogenic Tumours Springer Berlin Germany1992
[81] H Kumamoto and K Ooya ldquoDetection of mitochondria-mediated apoptosis signaling molecules in ameloblastomasrdquoJournal of Oral Pathology and Medicine vol 34 no 9 pp 565ndash572 2005
[82] H Kumamoto and K Ooya ldquoImmunohistochemical detectionof BH3-only proteins in ameloblastic tumorsrdquo Oral Diseasesvol 14 no 6 pp 550ndash555 2008
[83] H Kumamoto and K Ooya ldquoExpression of tumor necrosisfactor120572 TNF-related apoptosis-inducing ligand and their asso-ciated molecules in ameloblastomasrdquo Journal of Oral Pathologyand Medicine vol 34 no 5 pp 287ndash294 2005
[84] H Kumamoto K Kimi and K Ooya ldquoImmunohistochemicalanalysis of apoptosis-related factors (Fas Fas ligand caspase-3and single-stranded DNA) in ameloblastomasrdquo Journal of OralPathology and Medicine vol 30 no 10 pp 596ndash602 2001
[85] T E Carneiro S A Marinho F D Verli A T M Mesquita NL Lima and J L Miranda ldquoOral squamous papilloma clinicalhistologic and immunohistochemical analysesrdquo Journal of oralscience vol 51 no 3 pp 367ndash372 2009
[86] T Yamaguchi M Shindoh A Amemiya et al ldquoDetectionof human papillomavirus type 2 related sequence in oralpapillomardquo Analytical Cellular Pathology vol 16 no 3 pp 125ndash130 1998
[87] J H Main and M Pavone ldquoActinic cheilitis and carcinoma ofthe liprdquo Journal of Canadian Dental Association vol 60 no 2pp 113ndash116 1994
[88] A Martınez U Brethauer I G Rojas et al ldquoExpression ofapoptotic and cell proliferation regulatory proteins in actiniccheilitisrdquo Journal of Oral Pathology and Medicine vol 34 no5 pp 257ndash262 2005
[89] M A Birchall C MWinterford D J Allan and B V HarmonldquoApoptosis in normal epithelium premalignant and malignantlesions of the oropharynx and oral cavity a preliminary studyrdquoEuropean Journal of Cancer B vol 31 no 6 pp 380ndash383 1995
[90] N Tanda S Mori K Saito K Ikawa and S SakamotoldquoExpression of apoptotic signaling proteins in leukoplakia andoral lichen planus quantitative and topographical studiesrdquoJournal of Oral Pathology and Medicine vol 29 no 8 pp 385ndash393 2000
[91] G Kovesi and B Szende ldquoProgression of the leukoplakia isassociated to changes in apoptotic and mitotic index as well asin p53 and Ki-67 expressionrdquo Oncology vol 46 no 4 pp 333ndash338 2002
[92] H Tsuzuki S Fujieda H Sunaga N Narita M Tokuriki andH Saito ldquoExpression of p27 and apoptosis in oral leukoplakiardquoAnticancer Research vol 23 no 2 pp 1265ndash1270 2003
[93] E Chrysomali J S Greenspan N Dekker D Greenspanand J A Regezi ldquoApoptosis-associated proteins in oral hairyleukoplakiardquo Oral Diseases vol 2 no 4 pp 279ndash284 1996
[94] S H Kaufmann andG J Gores ldquoApoptosis in cancer cause andcurerdquo BioEssays vol 22 pp 1007ndash1017 2000
[95] S Ghavami M Hashemi S R Ande et al ldquoApoptosis andcancer mutations within caspase genesrdquo Journal of MedicalGenetics vol 46 no 8 pp 497ndash510 2009
[96] C M Coutinho-Camillo S V Lourenco I N NishimotoL P Kowalski and F A Soares ldquoCaspase expression in oralsquamous cell carcinomardquo Head and Neck vol 33 no 8 pp1191ndash1198 2011
[97] P J Polverini and J E Nor ldquoApoptosis and predisposition tooral cancerrdquo Critical Reviews in Oral Biology and Medicine vol10 no 2 pp 139ndash152 1999
[98] M Sulkowska W Famulski S Sulkowski et al ldquoCorrelationbetween Bcl-2 protein expression and some clinicopathologicalfeatures of oral squamous cell carcinomardquo Polish Journal ofPathology vol 54 no 1 pp 49ndash52 2003
[99] L L Loro O K Vintermyr P G Liavaag R Jonsson and A CJohannessen ldquoOral squamous cell carcinoma is associated withdecreased bcl-2bax expression ratio and increased apoptosisrdquoHuman Pathology vol 30 no 9 pp 1097ndash1105 1999
[100] M Baltaziak M KodaM Barwijuk-Machała et al ldquoThe role ofBak expression in apoptosis of the oral squamous cell carcinoma(OSCC) and metastases to lymph nodes (LNMs)rdquo AnnalesAcademiae Medicae Bialostocensis vol 49 pp 14ndash15 2004
[101] J C de Vicente L M J Gutierrez A H Zapatero M FF Forcelledo G Hernandez-Vallejo and J S Lopez ArranzldquoPrognostic significance of p53 expression in oral squamous cellcarcinoma without neck node metastasesrdquo Head and Neck vol26 no 1 pp 22ndash30 2004
[102] M A Gonzalez-Moles P Galindo J Gutierrez-Fernandez etal ldquoP53 protein expression in oral squamous cell carcinomasurvival analysisrdquo Anticancer Research vol 21 no 4 pp 2889ndash2894 2001
[103] S Kannan G Jagadeesh Chandran K Raveendran Pillai et alldquoExpression of p53 in leukoplakia and squamous cell carcinomaof the oral mucosa correlation with expression of Ki67rdquo Journalof Clinical Pathology vol 49 no 3 pp M170ndashM175 1996
[104] J Y Koh N P Cho G Kong J D Lee and K Yoon ldquop53mutations and human papillomavirus DNA in oral squamouscell carcinoma correlation with apoptosisrdquo British Journal ofCancer vol 78 no 3 pp 354ndash359 1998
[105] L LoMuzio G Pannone S Staibano et al ldquoSurvivin expressionin oral squamous cell carcinomardquo British Journal of Cancer vol89 no 12 pp 2244ndash2248 2003
[106] Y Jinbu K Tsukinoki N Miyagi et al ldquoExpression of survivinin oral squamous cell carcinomardquo Oral Med Pathol vol 11 pp41ndash44 2006
[107] C Jane A V Nerurkar N V Shirsat R B DeshpandeA D Amrapurkar and F R Karjodkar ldquoIncreased survivinexpression in high-grade oral squamous cell carcinoma a studyin Indian tobacco chewersrdquo Journal of Oral Pathology andMedicine vol 35 no 10 pp 595ndash601 2006
[108] Y-H Kim S-M Kim Y-K Kim S-P Hong M-J Kim andH Myoung ldquoEvaluation of survivin as a prognostic marker inoral squamous cell carcinomardquo Journal of Oral Pathology andMedicine vol 39 no 5 pp 368ndash375 2010
[109] N G Nikitakis J J Sauk and S I Papanicolaou ldquoThe role ofapoptosis in oral disease mechanisms aberrations in neoplas-tic autoimmune infectious hematologic and developmentaldiseases and therapeutic opportunitiesrdquo Oral Surgery OralMedicine Oral Pathology Oral Radiology and Endodontics vol97 no 4 pp 476ndash490 2004
[110] L L Loro O K Vintermyr A C Johannessen P G Liavaagand R Jonsson ldquoSuppression of Fas receptor and negative
Journal of Oral Diseases 11
correlation of Fas ligand with differentiation and apoptosis inoral squamous cell carcinomardquo Journal of Oral Pathology andMedicine vol 28 no 2 pp 82ndash87 1999
[111] N H Al-Rawi H Omer and S Al Kawas ldquoImmunohistochem-ical analysis of P53 and bcl-2 in benign and malignant salivaryglands tumorsrdquo Journal of Oral Pathology and Medicine vol 39no 1 pp 48ndash55 2010
[112] ANordkvist E Roijer G Bang et al ldquoExpression andmutationpatterns of p53 in benign andmalignant salivary gland tumorsrdquoInternational Journal of Oncology vol 16 no 3 pp 477ndash4832000
[113] V J Karja K J Syrjanen A-K Kurvinen and S M SyrjanenldquoExpression and mutations of p53 in salivary gland tumoursrdquoJournal of Oral Pathology and Medicine vol 26 no 5 pp 217ndash223 1997
[114] M Yanezez I Roa M Garcıa G Ibacache and M VillasecaldquoGene Bcl-2 protein expression in salivary gland tumorsrdquoRevista Medica de Chile vol 127 no 2 pp 139ndash142 1999
[115] L Jia R L Esguerra X Tang et al ldquoPrognostic value ofapoptosis and apoptosis-associated proteins in salivary glandadenoid cystic carcinomardquo Pathology International vol 54 no4 pp 217ndash223 2004
[116] Y Soini U Tormanen and P Paakko ldquoApoptosis is inverselyrelated to bcl-2 but not to bax expression in salivary glandtumoursrdquo Histopathology vol 32 no 1 pp 28ndash34 1998
[117] R M Nagler H Kerner S Ben-Eliezer I Minkov and O Ben-Itzhak ldquoPrognostic role of apoptotic Bcl-2 c-erbB-2 and p53tumor markers in salivary gland malignanciesrdquo Oncology vol64 no 4 pp 389ndash398 2003
odontogenic epithelium and is characterized by a benign butlocally invasive behavior with a high risk of recurrence [80]
RT-PCR and IHC showed expression of cytochrome cAPAF-1 caspase-9 and AIF in tooth germs and benign andmalignant ameloblastomas suggesting that themitochondria-mediated apoptotic pathway has a role in apoptotic celldeath of normal and neoplastic odontogenic epithelium andmight be involved in oncogenesis cytodifferentiation andmalignant transformation of odontogenic epithelium [81]
Granular cells basal cells desmoplastic ameloblastomasand ameloblastic carcinomas showed immunoreactivity forthe BH3-only proteins (Bid Bim Bad Noxa and Puma)whereas keratinising cells of acanthomatous ameloblastomasshowed no reactivity suggesting that these proteins mightbe involved in tumor cell differentiation of ameloblastomas[82] TNF-120572 TRAIL and their receptors were also found tobe expressed in tooth germs and ameloblastomas provingtheir role in cytodifferentiation of odontogenic epitheliumand tissue structuring of ameloblastomas [83] Similarlyexpression of Fas FasL caspase-3 and ssDNA has also beendemonstrated in various patterns in tooth germs and benignand malignant ameloblastomas [84]
352 Apoptosis and Benign Epithelial Tumor
(1) Apoptosis and Squamous PapillomaOral squamous papil-loma (OSP) is a frequent benign tumorous lesion associatedwith HPV OSP consists of proliferation of the stratifiedsquamous epithelium resulting in a papillary or verrucousexophytic mass and has got site predilection for the tongueand soft palate but any surface of the oral cavity can beaffected [85 86] Carneiro et al performed immunohisto-chemical assay on 12 OSP cases utilizing BP53-12 and Pab240antibodies for p53 protein and found that immunostainingfor protein p53 was primarily negative or weakly positivein all cases (in all epithelial layers) except one case whichindicates the benign nature of the lesions evidenced by theirslow development and less chances of becoming malignantIntense staining in one slide for both immunomarkers in allthe epithelial layers could be attributed to the presence ofvirus with high oncogenic potential (HPV 16 and 18) or tothe presence of coexisting external factors [85]
36 Apoptosis and Premalignant and Malignant Entities
361 Apoptosis and Actinic Cheilitis Actinic cheilitis (AC) isa common condition caused by damage to the lips throughexposure to sunlight and has the potential to undergomalignant transformation into squamous cell carcinoma [87]Overexpression of p53 was found in AC as compared tonormal lip and oral mucosa Bcl-2 expression was higherin AC than in oral mucosa but it was significantly reducedas compared with normal lip Thus it was suggested thatDNA-damaged cells by UV radiation in AC are eliminatedby apoptosis Also both p53 and bcl-2 play an important rolein regulating malignant transformation in AC [88]
362 Apoptosis and Oral Leukoplakia It has been sug-gested that a change in apoptosis accompanies the onset
of invasion in a premalignant lesion of the human oralcavity and oropharynx AI increased progressively fromnormal to carcinoma in situ (CIS) but fell in SCC withmaximum apoptotic index (AI) mitotic index (MI) ratioin CIS The position of apoptotic bodies was localised tothe deepest layers in normal and dysplastic epithelia butbecame generalised in CIS and SCC [89] Greater expressionof oncoproteins MDM2 and Bcl-2 was seen in leukoplakiawith altered keratinocyte maturation than OLP case whereasexpression of wt-p53 and p21 was higher in OLP compared toleukoplakia cases In spite of divergent outcome of apoptoticsignalling proteins no significant difference in the number ofapoptotic epithelial cells was observed between leukoplakiaand OLP cases [90] Increased mitotic apoptotic and Ki-67 index indicate unfavourable prognosis of leukoplakia [91]Abundance of p27 expression in oral leukoplakia may beassociated with inhibition of cell proliferation leading toapoptosis of premalignant tumor cells thus preventing tumorprogression [92] It is hypothesised that the antiapoptoticability of Epstein-Barr virus (EBV) may result in alteredexpression of apoptosis-associated proteins in oral hairyleukoplakia Except p53 which appears to be overexpressedthere is only slight alteration in immunoexpression of otherapoptosis-associated proteins in OHL [93]
363 Apoptosis and Oral Squamous Cell Carcinoma Theaccumulation of neoplastic cells can occur through enhancedproliferation diminished cell turnover or a combination ofboth processes Tumor cells from a wide variety of humancancers have been shown to exhibit increased survival andresistance to apoptosis [94] There are two major ways thatcould downregulate cancer cell apoptosis (1) somatic andnonsomatic mutation and loss of expression of proapoptoticmolecules and (2) overexpression of apoptosis inhibitorymolecules Mutations within caspase family proteases are notuncommon in malignancies [95] Caspase-7 proved to bean independent prognosticator and predictor of locoregionalrecurrence in patients of OSCC [96] Several alterations thatinhibit both the death receptor and mitochondrial pathwaysvia caspases have also been identified including overexpres-sion of IAPs activation of PI3k or Akt and posttranslationalmodifications of caspases [94]
In pathological settings Bcl-2 gene family appears toact synergistically with oncogenes and tumor suppressorgenes [97] Positive Bcl-2 expression is associated with highertumor grading higher tumor mitotic index higher index ofatypical mitoses and microfocal pattern of tumor invasivemargins [98] In OSCC compared with oral epitheliumthere is a decreased Bcl-2 expression a lowered Bcl-2Baxratio and increased apoptosis Expression of Bax correlatedwith histological tumor grading in OSCC [99] whereasothers found that expression of Bak may be useful for bettercharacterizing and predicting the prognosis of OSCC [100]
Aberrations of the p53 gene and overexpression of its pro-tein are widely recognized markers of malignancy includingOSCC It was found that there is a negative correlation of p53immunoexpression with histologic grade of differentiationIn patients without neck node metastases p53 showed astrong correlation with survival [101] On the contrary
Journal of Oral Diseases 7
another study showed that expression of p53 protein did notbehave as amarker of prognostic value in patients withOSCC[102]
As cancer is characterized by uncontrolled cell prolif-eration markers of proliferation such as Ki67 and PCNAhave been studied extensively in neoplastic lesions Expres-sion of both p53 and Ki67 correlated significantly with thehistopathological stage of the tumor However expression ofp53 was not correlated with that of Ki67 [103]
HPV infection andor p53 mutations are implicated incarcinogenesis of oral SCC but are not mutually exclusiveevents Moreover decrease in apoptosis is more closelyrelated to p53 mutation than HPV infection [104]
Survivin has got a versatile role in modulating celldivision and apoptosis in cancer Low survivin expressioncorrelated statistically significantly with better survival ratesbut not with age sex tumor size the presence of lymphnode or distant metastases [105] Survivin was found tobe preferentially expressed in nonadvanced nonmetastaticand chemotherapy-sensitive OSCC [106] On the contraryincreased expression of survivin was found in high-gradetumors suggesting its contribution to apoptosis resistancein response to therapy [107] Also significant correlationbetween survivin expression lymph node metastasis andproliferation was revealed but not with differentiationmicrovessel density or TNM staging [108]
Upregulation of FasL and downregulation of Fas havebeen shown to occur in oral carcinogenesis possibly con-tributing to both cancer cell survival and evasion of the hostimmune assault through induction of apoptosis in T cellsthat would normally kill tumor cells [109] Moreover it hasbeen found that Fas is expressed in low quantities in OSCCwhereas FasL expression correlates negatively with degree ofdifferentiation and apoptosis in OSCC [110] Thus variousproteins (apoptotic and antiapoptotic) have got a significantbearing in initiation progression and prognosis of OSCC
37 Apoptosis and Salivary Gland Tumors Salivary glandtumors (SGT) are relatively uncommon neoplasms withwidely variable histopathologic and biologic characteristicsP53bcl-2 immunostaining reactivity could be helpful indemonstrating SGT behavior in terms of progression andextent of invasion since all malignant salivary gland tumorswere positive whereas 70 of pleomorphic adenomas (PA)showed negative expression [111] Similarly Nordkvist et alfound p53 overexpression in 20 of the malignant SGT withthe highest prevalence in PLGA squamous cell carcinomaand CaXPA and the lowest in adenoid cystic carcinomaand acinic cell carcinoma but none of the benign PA [112]Expression of p53 in malignant tumors bore no correlationto local recurrence metastatic disease or survival of thepatients [113] Bcl-2 protein expression was found virtuallyin all benign and malignant SGT suggesting its role in thedevelopment and proliferation of these tumors via inhibitionof apoptosis [114] p53 expression apoptotic index and bcl-2 protein are potential prognostic parameters in salivarygland adenoid cystic carcinoma [115] Frequency of apoptosisis inversely related to bcl-2 but not to Bax expression inSGT [116] Survival probability of patients who demonstrated
positive staining for c-erbB-2 or TUNEL or both was lowerthan those with negative staining [117]
4 Conclusion
Understanding the mechanistic machinery of apoptosis iscrucial because it influences both health and disease beinginitiated by various physiologic and pathologic stimuliMore-over the extensive involvement of apoptosis in the patho-genesis of various oral diseases and meticulous knowledgeabout it prompt it to therapeutic intervention at differentcheckpoints This review is an attempt to provide an updateon the crucial role and importance of apoptosis in various oralpathologies
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
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[2] J F Kerr A H Wyllie and A R Currie ldquoApoptosis abasic biological phenomenon with wide-ranging implicationsin tissue kineticsrdquo British Journal of Cancer vol 26 no 4 pp239ndash257 1972
[3] A Strasser L OrsquoConnor and V M Dixit ldquoApoptosis signalingrdquoAnnual Review of Biochemistry vol 69 pp 217ndash245 2000
[4] N Singh ldquoApoptosis in health and disease and modulation ofapoptosis for therapy an overviewrdquo Indian Journal of ClinicalBiochemistry vol 22 no 2 pp 6ndash16 2007
[5] T-J Fan L-H Han R-S Cong and J Liang ldquoCaspase familyproteases and apoptosisrdquo Acta Biochimica et Biophysica Sinicavol 37 no 11 pp 719ndash727 2005
[6] P C Ashe and M D Berry ldquoApoptotic signaling cascadesrdquoProgress in Neuro-Psychopharmacology and Biological Psychia-try vol 27 no 2 pp 199ndash214 2003
[7] L L Loro O K Vintermyr and A C Johannessen ldquoApoptosisin normal and diseased oral tissuesrdquoOral Diseases vol 11 no 5pp 274ndash287 2005
[8] H Jafarzadeh M Sanatkhani and N Mohtasham ldquoOral pyo-genic granuloma a reviewrdquo Journal of Oral Science vol 48 no4 pp 167ndash175 2006
[9] T Nakamura ldquoApoptosis and expression of BaxBcl-2 proteinsin pyogenic granuloma a comparative study with granulationtissue and capillary hemangiomardquo Journal of Cutaneous Pathol-ogy vol 27 no 8 pp 400ndash405 2000
[10] K Yuan L-Y C Wing and M T Lin ldquoPathogenetic roles ofangiogenic factors in pyogenic granulomas in pregnancy aremodulated by female sex hormonesrdquo Journal of Periodontologyvol 73 no 7 pp 701ndash708 2002
[11] K Yuan and M T Lin ldquoThe roles of vascular endothelialgrowth factor and angiopoietin-2 in the regression of pregnancypyogenic granulomardquo Oral Diseases vol 10 no 3 pp 179ndash1852004
[12] F R Amaral V F Bernardes A P Duarte et al ldquoQuantitativeexpression analysis of apoptoticantiapoptotic genes and associ-ationwith immunolocalization of BAX andBCL-2 in peripheral
8 Journal of Oral Diseases
and central giant cell lesions of the jawsrdquo Tumor Biology vol 32no 5 pp 997ndash1003 2011
[13] J Pammer W Weninger H Hulla P Mazal and R HorvatldquoExpression of regulatory apoptotic proteins in peripheral giantcell granulomas and lesions containing osteoclast-like giantcellsrdquo Journal of Oral Pathology and Medicine vol 27 no 6 pp267ndash271 1998
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[15] T Honma T Saito and Y Fujioka ldquoPossible role of apoptoticcells of the oral epithelium in the pathogenesis of aphthousulcerationrdquoOral Surgery Oral Medicine and Oral Pathology vol59 no 4 pp 379ndash387 1985
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[17] J Gamonal A Bascones A Acevedo E Blanco and A SilvaldquoApoptosis in chronic adult periodontitis analyzed by in situDNA breaks electron microscopy and immunohistochem-istryrdquo Journal of Periodontology vol 72 no 4 pp 517ndash525 2001
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[19] P Kelk A Johansson R Claesson L Hanstrom and S KalfasldquoCaspase 1 involvement in human monocyte lysis induced byActinobacillus actinomycetemcomitans leukotoxinrdquo Infectionand Immunity vol 71 no 8 pp 4448ndash4455 2003
[20] P G Stathopoulou J C Galicia M R Benakanakere C AGarcia J Potempa and D F Kinane ldquoPorphyromonas gingi-valis induce apoptosis in human gingival epithelial cells througha gingipain-dependent mechanismrdquo BMC Microbiology vol 9article 107 2009
[21] T Murata K YaegakiW Qian et al ldquoHydrogen sulfide inducesapoptosis in epithelial cells derived from human gingivalrdquoJournal of Breath Research vol 2 no 1 Article ID 017007 2008
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[24] VAMurrah andE PGilchrist ldquoAssessment of apoptosis in orallichen planusrdquoOral Surgery OralMedicine Oral Pathology OralRadiology and Endodontics vol 82 no 2 pp 209ndash210 1996
[25] M R Roopashree R V Gondhalekar M C Shashikanth JGeorge S H Thippeswamy and A Shukla ldquoPathogenesis oforal lichen planus a reviewrdquo Journal of Oral Pathology andMedicine vol 39 no 10 pp 729ndash734 2010
[26] R Mattila and S Syrjanen ldquoCaspase cascade pathways inapoptosis of oral lichen planusrdquo Oral Surgery Oral MedicineOral Pathology Oral Radiology and Endodontology vol 110 no5 pp 618ndash623 2010
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[34] R Abe T Shimizu A Shibaki H Nakamura HWatanabe andH Shimizu ldquoToxic epidermal necrolysis and Stevens-Johnsonsyndrome are induced by soluble fas ligandrdquo The AmericanJournal of Pathology vol 162 no 5 pp 1515ndash1520 2003
[35] S Inachi H Mizutani and M Shimizu ldquoEpidermal apop-totic cell death in erythema multiforme and Stevens-Johnsonsyndrome contribution of perforin-positive cell infiltrationrdquoArchives of Dermatology vol 133 no 7 pp 845ndash849 1997
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[37] S White and A Rosen ldquoApoptosis in systemic lupus erythe-matosusrdquo Current Opinion in Rheumatology vol 15 no 5 pp557ndash562 2003
[38] D Shah S Sah and S K Nath ldquoInteraction between glu-tathione and apoptosis in systemic lupus erythematosusrdquoAutoimmunity Reviews vol 12 no 7 pp 741ndash751 2013
[39] S Rajagopalan E C Somers R D Brook et al ldquoEndothelial cellapoptosis in systemic lupus erythematosus a common pathwayfor abnormal vascular function and thrombosis propensityrdquoBlood vol 103 no 10 pp 3677ndash3683 2004
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[45] K Yoneda T Furukawa Y-J Zheng et al ldquoAn autocrineparacrine loop linking keratin 14 aggregates to tumor necrosisdactor 120572-mediated cytotoxicity in a keratinocyte model ofepidermolysis bullosa simplexrdquo Journal of Biological Chemistryvol 279 no 8 pp 7296ndash7303 2004
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[47] T A Graubert J H Russell and T J Ley ldquoThe role of granzymeB in murine models of acute graft-versus-host disease and graftrejectionrdquo Blood vol 87 no 4 pp 1232ndash1237 1996
[48] N Zavazava and D Kabelitz ldquoAlloreactivity and apoptosisin graft rejection and transplantation tolerancerdquo Journal ofLeukocyte Biology vol 68 no 2 pp 167ndash174 2000
[49] A Sarin E KHaddad and PAHenkart ldquoCaspase dependenceof target cell damage induced by cytotoxic lymphocytesrdquo Jour-nal of Immunology vol 161 no 6 pp 2810ndash2816 1998
[50] M Enari H Hug and S Nagata ldquoInvolvement of an ICE-likeprotease in Fas-mediated apoptosisrdquo Nature vol 375 no 6526pp 78ndash81 1995
[51] T H Holmstrom and J E Eriksson ldquoPhophorylation basedsignaling in Fas receptor mediated apoptosisrdquo Critical Reviewsin Immunology vol 20 pp 121ndash152 2000
[52] Y H Yoo A C Gilliam D Whitaker-Menezes R Korngoldand G F Murphy ldquoExperimental induction and ultrastructuralcharacterization of apoptosis in marine acute cutaneous graft-versus-host diseaserdquo Archives of Dermatological Research vol289 no 7 pp 389ndash398 1997
[53] Y Hayashi K Yayagi and N Haneji ldquoInvolvement of apoptoticprotease cascade for tissue destruction in Sjogrenrsquos syndromerdquoArchivum Immunologiae et Therapiae Experimentalis vol 48no 5 pp 399ndash403 2000
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[56] M Ohlsson K Skarstein A I Bolstad A C Johannessen andR Jonsson ldquoFas-induced apoptosis is a rare event in Sjogrenrsquossyndromerdquo Laboratory Investigation vol 81 no 1 pp 95ndash1052001
[57] M Sisto S Lisi D Lofrumento M DrsquoAmore P Scagliusiand VMitolo ldquoAutoantibodies from Sjogrenrsquos syndrome triggerapoptosis in salivary gland cell linerdquo Annals of the New YorkAcademy of Sciences vol 1108 pp 418ndash425 2007
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[59] B M Polster J Pevsner and J M Hardwick ldquoViral Bcl-2homologs and their role in virus replication and associateddiseasesrdquo Biochimica et Biophysica Acta vol 1644 no 2-3 pp211ndash227 2004
[60] S Cooray ldquoThe pivotal role of phosphatidylinositol 3-kinase-Akt signal transduction in virus survivalrdquo Journal of GeneralVirology vol 85 no 5 pp 1065ndash1076 2004
[61] J G Teodoro andP E Branton ldquoRegulation of apoptosis by viralgene productsrdquo Journal of Virology vol 71 no 3 pp 1739ndash17461997
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[64] L Aurelian ldquoHSV-induced apoptosis in herpes encephalitisrdquoCurrent Topics in Microbiology and Immunology vol 289 pp79ndash111 2005
[65] J Ennaciri J Menezes F Proulx and B J Toledano ldquoInductionof apoptosis by herpes simplex virus-1 in neonatal but not adultneutrophilsrdquo Pediatric Research vol 59 no 1 pp 7ndash12 2006
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[71] T Suzuki H Kumamoto K Kunimori andKOoya ldquoImmuno-histochemical analysis of apoptosis-related factors in liningepithelium of radicular cystsrdquo Journal of Oral Pathology andMedicine vol 34 no 1 pp 46ndash52 2005
[72] C A Martins E R C Rivero R M Dufloth C P Figueiredoand D S C Vieira ldquoImmunohistochemical detection of factorsrelated to cellular proliferation and apoptosis in radicular anddentigerous cystsrdquo Journal of Endodontics vol 37 no 1 pp 36ndash39 2011
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[74] A Piattelli M Fioroni and C Rubini ldquoDifferentiation ofodontogenic keratocysts from other odontogenic cysts by theexpression of bcl-2 immunoreactivityrdquo Oral Oncology vol 34no 5 pp 404ndash407 1998
[75] G C P Mateus G H D S P Lanza P H R deMoura H A deMarigo and M C R Horta ldquoCell proliferation and apoptosisin keratocystic odontogenic tumorsrdquo Medicina Oral PatologiaOral y Cirugia Bucal vol 13 no 11 pp E697ndashE702 2008
[76] L Artese A Piattelli C Rubini et al ldquop16 expression inodontogenic tumorsrdquo Tumori vol 94 no 5 pp 718ndash723 2008
[77] L Lo Muzio S Staibano G Pannone et al ldquoExpression of cellcycle and apoptosis-related proteins in sporadic odontogenickeratocysts and odontogenic keratocysts associated with thenevoid basal cell carcinoma syndromerdquo Journal of DentalResearch vol 78 no 7 pp 1345ndash1353 1999
10 Journal of Oral Diseases
[78] D K Kim S G Ahn J Kim and J H Yoon ldquoComparativeKi-67 expression and apoptosis in the odontogenic keratocystassociated with or without an impacted tooth in addition tounilocular and multilocular varietiesrdquo Yonsei Medical Journalvol 44 no 5 pp 841ndash846 2003
[79] M Andric B Dozic B Popovic et al ldquoSurvivin expression inodontogenic keratocysts and correlation with cytomegalovirusinfectionrdquo Oral Diseases vol 16 no 2 pp 156ndash159 2010
[80] I R H Kramer J J Pindborg and M ShearWHOHistologicalTyping of Odontogenic Tumours Springer Berlin Germany1992
[81] H Kumamoto and K Ooya ldquoDetection of mitochondria-mediated apoptosis signaling molecules in ameloblastomasrdquoJournal of Oral Pathology and Medicine vol 34 no 9 pp 565ndash572 2005
[82] H Kumamoto and K Ooya ldquoImmunohistochemical detectionof BH3-only proteins in ameloblastic tumorsrdquo Oral Diseasesvol 14 no 6 pp 550ndash555 2008
[83] H Kumamoto and K Ooya ldquoExpression of tumor necrosisfactor120572 TNF-related apoptosis-inducing ligand and their asso-ciated molecules in ameloblastomasrdquo Journal of Oral Pathologyand Medicine vol 34 no 5 pp 287ndash294 2005
[84] H Kumamoto K Kimi and K Ooya ldquoImmunohistochemicalanalysis of apoptosis-related factors (Fas Fas ligand caspase-3and single-stranded DNA) in ameloblastomasrdquo Journal of OralPathology and Medicine vol 30 no 10 pp 596ndash602 2001
[85] T E Carneiro S A Marinho F D Verli A T M Mesquita NL Lima and J L Miranda ldquoOral squamous papilloma clinicalhistologic and immunohistochemical analysesrdquo Journal of oralscience vol 51 no 3 pp 367ndash372 2009
[86] T Yamaguchi M Shindoh A Amemiya et al ldquoDetectionof human papillomavirus type 2 related sequence in oralpapillomardquo Analytical Cellular Pathology vol 16 no 3 pp 125ndash130 1998
[87] J H Main and M Pavone ldquoActinic cheilitis and carcinoma ofthe liprdquo Journal of Canadian Dental Association vol 60 no 2pp 113ndash116 1994
[88] A Martınez U Brethauer I G Rojas et al ldquoExpression ofapoptotic and cell proliferation regulatory proteins in actiniccheilitisrdquo Journal of Oral Pathology and Medicine vol 34 no5 pp 257ndash262 2005
[89] M A Birchall C MWinterford D J Allan and B V HarmonldquoApoptosis in normal epithelium premalignant and malignantlesions of the oropharynx and oral cavity a preliminary studyrdquoEuropean Journal of Cancer B vol 31 no 6 pp 380ndash383 1995
[90] N Tanda S Mori K Saito K Ikawa and S SakamotoldquoExpression of apoptotic signaling proteins in leukoplakia andoral lichen planus quantitative and topographical studiesrdquoJournal of Oral Pathology and Medicine vol 29 no 8 pp 385ndash393 2000
[91] G Kovesi and B Szende ldquoProgression of the leukoplakia isassociated to changes in apoptotic and mitotic index as well asin p53 and Ki-67 expressionrdquo Oncology vol 46 no 4 pp 333ndash338 2002
[92] H Tsuzuki S Fujieda H Sunaga N Narita M Tokuriki andH Saito ldquoExpression of p27 and apoptosis in oral leukoplakiardquoAnticancer Research vol 23 no 2 pp 1265ndash1270 2003
[93] E Chrysomali J S Greenspan N Dekker D Greenspanand J A Regezi ldquoApoptosis-associated proteins in oral hairyleukoplakiardquo Oral Diseases vol 2 no 4 pp 279ndash284 1996
[94] S H Kaufmann andG J Gores ldquoApoptosis in cancer cause andcurerdquo BioEssays vol 22 pp 1007ndash1017 2000
[95] S Ghavami M Hashemi S R Ande et al ldquoApoptosis andcancer mutations within caspase genesrdquo Journal of MedicalGenetics vol 46 no 8 pp 497ndash510 2009
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[97] P J Polverini and J E Nor ldquoApoptosis and predisposition tooral cancerrdquo Critical Reviews in Oral Biology and Medicine vol10 no 2 pp 139ndash152 1999
[98] M Sulkowska W Famulski S Sulkowski et al ldquoCorrelationbetween Bcl-2 protein expression and some clinicopathologicalfeatures of oral squamous cell carcinomardquo Polish Journal ofPathology vol 54 no 1 pp 49ndash52 2003
[99] L L Loro O K Vintermyr P G Liavaag R Jonsson and A CJohannessen ldquoOral squamous cell carcinoma is associated withdecreased bcl-2bax expression ratio and increased apoptosisrdquoHuman Pathology vol 30 no 9 pp 1097ndash1105 1999
[100] M Baltaziak M KodaM Barwijuk-Machała et al ldquoThe role ofBak expression in apoptosis of the oral squamous cell carcinoma(OSCC) and metastases to lymph nodes (LNMs)rdquo AnnalesAcademiae Medicae Bialostocensis vol 49 pp 14ndash15 2004
[101] J C de Vicente L M J Gutierrez A H Zapatero M FF Forcelledo G Hernandez-Vallejo and J S Lopez ArranzldquoPrognostic significance of p53 expression in oral squamous cellcarcinoma without neck node metastasesrdquo Head and Neck vol26 no 1 pp 22ndash30 2004
[102] M A Gonzalez-Moles P Galindo J Gutierrez-Fernandez etal ldquoP53 protein expression in oral squamous cell carcinomasurvival analysisrdquo Anticancer Research vol 21 no 4 pp 2889ndash2894 2001
[103] S Kannan G Jagadeesh Chandran K Raveendran Pillai et alldquoExpression of p53 in leukoplakia and squamous cell carcinomaof the oral mucosa correlation with expression of Ki67rdquo Journalof Clinical Pathology vol 49 no 3 pp M170ndashM175 1996
[104] J Y Koh N P Cho G Kong J D Lee and K Yoon ldquop53mutations and human papillomavirus DNA in oral squamouscell carcinoma correlation with apoptosisrdquo British Journal ofCancer vol 78 no 3 pp 354ndash359 1998
[105] L LoMuzio G Pannone S Staibano et al ldquoSurvivin expressionin oral squamous cell carcinomardquo British Journal of Cancer vol89 no 12 pp 2244ndash2248 2003
[106] Y Jinbu K Tsukinoki N Miyagi et al ldquoExpression of survivinin oral squamous cell carcinomardquo Oral Med Pathol vol 11 pp41ndash44 2006
[107] C Jane A V Nerurkar N V Shirsat R B DeshpandeA D Amrapurkar and F R Karjodkar ldquoIncreased survivinexpression in high-grade oral squamous cell carcinoma a studyin Indian tobacco chewersrdquo Journal of Oral Pathology andMedicine vol 35 no 10 pp 595ndash601 2006
[108] Y-H Kim S-M Kim Y-K Kim S-P Hong M-J Kim andH Myoung ldquoEvaluation of survivin as a prognostic marker inoral squamous cell carcinomardquo Journal of Oral Pathology andMedicine vol 39 no 5 pp 368ndash375 2010
[109] N G Nikitakis J J Sauk and S I Papanicolaou ldquoThe role ofapoptosis in oral disease mechanisms aberrations in neoplas-tic autoimmune infectious hematologic and developmentaldiseases and therapeutic opportunitiesrdquo Oral Surgery OralMedicine Oral Pathology Oral Radiology and Endodontics vol97 no 4 pp 476ndash490 2004
[110] L L Loro O K Vintermyr A C Johannessen P G Liavaagand R Jonsson ldquoSuppression of Fas receptor and negative
Journal of Oral Diseases 11
correlation of Fas ligand with differentiation and apoptosis inoral squamous cell carcinomardquo Journal of Oral Pathology andMedicine vol 28 no 2 pp 82ndash87 1999
[111] N H Al-Rawi H Omer and S Al Kawas ldquoImmunohistochem-ical analysis of P53 and bcl-2 in benign and malignant salivaryglands tumorsrdquo Journal of Oral Pathology and Medicine vol 39no 1 pp 48ndash55 2010
[112] ANordkvist E Roijer G Bang et al ldquoExpression andmutationpatterns of p53 in benign andmalignant salivary gland tumorsrdquoInternational Journal of Oncology vol 16 no 3 pp 477ndash4832000
[113] V J Karja K J Syrjanen A-K Kurvinen and S M SyrjanenldquoExpression and mutations of p53 in salivary gland tumoursrdquoJournal of Oral Pathology and Medicine vol 26 no 5 pp 217ndash223 1997
[114] M Yanezez I Roa M Garcıa G Ibacache and M VillasecaldquoGene Bcl-2 protein expression in salivary gland tumorsrdquoRevista Medica de Chile vol 127 no 2 pp 139ndash142 1999
[115] L Jia R L Esguerra X Tang et al ldquoPrognostic value ofapoptosis and apoptosis-associated proteins in salivary glandadenoid cystic carcinomardquo Pathology International vol 54 no4 pp 217ndash223 2004
[116] Y Soini U Tormanen and P Paakko ldquoApoptosis is inverselyrelated to bcl-2 but not to bax expression in salivary glandtumoursrdquo Histopathology vol 32 no 1 pp 28ndash34 1998
[117] R M Nagler H Kerner S Ben-Eliezer I Minkov and O Ben-Itzhak ldquoPrognostic role of apoptotic Bcl-2 c-erbB-2 and p53tumor markers in salivary gland malignanciesrdquo Oncology vol64 no 4 pp 389ndash398 2003
another study showed that expression of p53 protein did notbehave as amarker of prognostic value in patients withOSCC[102]
As cancer is characterized by uncontrolled cell prolif-eration markers of proliferation such as Ki67 and PCNAhave been studied extensively in neoplastic lesions Expres-sion of both p53 and Ki67 correlated significantly with thehistopathological stage of the tumor However expression ofp53 was not correlated with that of Ki67 [103]
HPV infection andor p53 mutations are implicated incarcinogenesis of oral SCC but are not mutually exclusiveevents Moreover decrease in apoptosis is more closelyrelated to p53 mutation than HPV infection [104]
Survivin has got a versatile role in modulating celldivision and apoptosis in cancer Low survivin expressioncorrelated statistically significantly with better survival ratesbut not with age sex tumor size the presence of lymphnode or distant metastases [105] Survivin was found tobe preferentially expressed in nonadvanced nonmetastaticand chemotherapy-sensitive OSCC [106] On the contraryincreased expression of survivin was found in high-gradetumors suggesting its contribution to apoptosis resistancein response to therapy [107] Also significant correlationbetween survivin expression lymph node metastasis andproliferation was revealed but not with differentiationmicrovessel density or TNM staging [108]
Upregulation of FasL and downregulation of Fas havebeen shown to occur in oral carcinogenesis possibly con-tributing to both cancer cell survival and evasion of the hostimmune assault through induction of apoptosis in T cellsthat would normally kill tumor cells [109] Moreover it hasbeen found that Fas is expressed in low quantities in OSCCwhereas FasL expression correlates negatively with degree ofdifferentiation and apoptosis in OSCC [110] Thus variousproteins (apoptotic and antiapoptotic) have got a significantbearing in initiation progression and prognosis of OSCC
37 Apoptosis and Salivary Gland Tumors Salivary glandtumors (SGT) are relatively uncommon neoplasms withwidely variable histopathologic and biologic characteristicsP53bcl-2 immunostaining reactivity could be helpful indemonstrating SGT behavior in terms of progression andextent of invasion since all malignant salivary gland tumorswere positive whereas 70 of pleomorphic adenomas (PA)showed negative expression [111] Similarly Nordkvist et alfound p53 overexpression in 20 of the malignant SGT withthe highest prevalence in PLGA squamous cell carcinomaand CaXPA and the lowest in adenoid cystic carcinomaand acinic cell carcinoma but none of the benign PA [112]Expression of p53 in malignant tumors bore no correlationto local recurrence metastatic disease or survival of thepatients [113] Bcl-2 protein expression was found virtuallyin all benign and malignant SGT suggesting its role in thedevelopment and proliferation of these tumors via inhibitionof apoptosis [114] p53 expression apoptotic index and bcl-2 protein are potential prognostic parameters in salivarygland adenoid cystic carcinoma [115] Frequency of apoptosisis inversely related to bcl-2 but not to Bax expression inSGT [116] Survival probability of patients who demonstrated
positive staining for c-erbB-2 or TUNEL or both was lowerthan those with negative staining [117]
4 Conclusion
Understanding the mechanistic machinery of apoptosis iscrucial because it influences both health and disease beinginitiated by various physiologic and pathologic stimuliMore-over the extensive involvement of apoptosis in the patho-genesis of various oral diseases and meticulous knowledgeabout it prompt it to therapeutic intervention at differentcheckpoints This review is an attempt to provide an updateon the crucial role and importance of apoptosis in various oralpathologies
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] A Lawen ldquoApoptosis an introductionrdquo BioEssays vol 25 no 9pp 888ndash896 2003
[2] J F Kerr A H Wyllie and A R Currie ldquoApoptosis abasic biological phenomenon with wide-ranging implicationsin tissue kineticsrdquo British Journal of Cancer vol 26 no 4 pp239ndash257 1972
[3] A Strasser L OrsquoConnor and V M Dixit ldquoApoptosis signalingrdquoAnnual Review of Biochemistry vol 69 pp 217ndash245 2000
[4] N Singh ldquoApoptosis in health and disease and modulation ofapoptosis for therapy an overviewrdquo Indian Journal of ClinicalBiochemistry vol 22 no 2 pp 6ndash16 2007
[5] T-J Fan L-H Han R-S Cong and J Liang ldquoCaspase familyproteases and apoptosisrdquo Acta Biochimica et Biophysica Sinicavol 37 no 11 pp 719ndash727 2005
[6] P C Ashe and M D Berry ldquoApoptotic signaling cascadesrdquoProgress in Neuro-Psychopharmacology and Biological Psychia-try vol 27 no 2 pp 199ndash214 2003
[7] L L Loro O K Vintermyr and A C Johannessen ldquoApoptosisin normal and diseased oral tissuesrdquoOral Diseases vol 11 no 5pp 274ndash287 2005
[8] H Jafarzadeh M Sanatkhani and N Mohtasham ldquoOral pyo-genic granuloma a reviewrdquo Journal of Oral Science vol 48 no4 pp 167ndash175 2006
[9] T Nakamura ldquoApoptosis and expression of BaxBcl-2 proteinsin pyogenic granuloma a comparative study with granulationtissue and capillary hemangiomardquo Journal of Cutaneous Pathol-ogy vol 27 no 8 pp 400ndash405 2000
[10] K Yuan L-Y C Wing and M T Lin ldquoPathogenetic roles ofangiogenic factors in pyogenic granulomas in pregnancy aremodulated by female sex hormonesrdquo Journal of Periodontologyvol 73 no 7 pp 701ndash708 2002
[11] K Yuan and M T Lin ldquoThe roles of vascular endothelialgrowth factor and angiopoietin-2 in the regression of pregnancypyogenic granulomardquo Oral Diseases vol 10 no 3 pp 179ndash1852004
[12] F R Amaral V F Bernardes A P Duarte et al ldquoQuantitativeexpression analysis of apoptoticantiapoptotic genes and associ-ationwith immunolocalization of BAX andBCL-2 in peripheral
8 Journal of Oral Diseases
and central giant cell lesions of the jawsrdquo Tumor Biology vol 32no 5 pp 997ndash1003 2011
[13] J Pammer W Weninger H Hulla P Mazal and R HorvatldquoExpression of regulatory apoptotic proteins in peripheral giantcell granulomas and lesions containing osteoclast-like giantcellsrdquo Journal of Oral Pathology and Medicine vol 27 no 6 pp267ndash271 1998
[14] C Scully and S Porter ldquoOral mucosal disease recurrentaphthous stomatitisrdquo British Journal of Oral and MaxillofacialSurgery vol 46 no 3 pp 198ndash206 2008
[15] T Honma T Saito and Y Fujioka ldquoPossible role of apoptoticcells of the oral epithelium in the pathogenesis of aphthousulcerationrdquoOral Surgery Oral Medicine and Oral Pathology vol59 no 4 pp 379ndash387 1985
[16] J F N Pinto Rodrigues C T Fujiyama Oshima A P RibeiroPaiotti M Franco S S Miki Ihara and D A RibeiroldquoExpression of apoptosis regulatory proteins p53 bcl-2 andbax in recurrent aphthous ulcerationrdquo Journal of the EuropeanAcademy of Dermatology and Venereology vol 26 no 10 pp1247ndash1251 2012
[17] J Gamonal A Bascones A Acevedo E Blanco and A SilvaldquoApoptosis in chronic adult periodontitis analyzed by in situDNA breaks electron microscopy and immunohistochem-istryrdquo Journal of Periodontology vol 72 no 4 pp 517ndash525 2001
[18] F Jarnbring E Somogyi J Dalton A Gustafsson and BKlinge ldquoQuantitative assessment of apoptotic and prolifera-tive gingival keratinocytes in oral and sulcular epithelium inpatients with gingivitis and periodontitisrdquo Journal of ClinicalPeriodontology vol 29 no 12 pp 1065ndash1071 2002
[19] P Kelk A Johansson R Claesson L Hanstrom and S KalfasldquoCaspase 1 involvement in human monocyte lysis induced byActinobacillus actinomycetemcomitans leukotoxinrdquo Infectionand Immunity vol 71 no 8 pp 4448ndash4455 2003
[20] P G Stathopoulou J C Galicia M R Benakanakere C AGarcia J Potempa and D F Kinane ldquoPorphyromonas gingi-valis induce apoptosis in human gingival epithelial cells througha gingipain-dependent mechanismrdquo BMC Microbiology vol 9article 107 2009
[21] T Murata K YaegakiW Qian et al ldquoHydrogen sulfide inducesapoptosis in epithelial cells derived from human gingivalrdquoJournal of Breath Research vol 2 no 1 Article ID 017007 2008
[22] J C Galicia M R Benakanakere P G Stathopoulou and DF Kinane ldquoNeutrophils rescue gingival epithelial cells frombacterial-induced apoptosisrdquo Journal of Leukocyte Biology vol86 no 1 pp 181ndash186 2009
[23] A Kantarci P Augustin E Firatli et al ldquoApoptosis in gingivalovergrowth tissuesrdquo Journal of Dental Research vol 86 no 9pp 888ndash892 2007
[24] VAMurrah andE PGilchrist ldquoAssessment of apoptosis in orallichen planusrdquoOral Surgery OralMedicine Oral Pathology OralRadiology and Endodontics vol 82 no 2 pp 209ndash210 1996
[25] M R Roopashree R V Gondhalekar M C Shashikanth JGeorge S H Thippeswamy and A Shukla ldquoPathogenesis oforal lichen planus a reviewrdquo Journal of Oral Pathology andMedicine vol 39 no 10 pp 729ndash734 2010
[26] R Mattila and S Syrjanen ldquoCaspase cascade pathways inapoptosis of oral lichen planusrdquo Oral Surgery Oral MedicineOral Pathology Oral Radiology and Endodontology vol 110 no5 pp 618ndash623 2010
[27] J M C Brant A C Vasconcelos and L V Rodrigues ldquoRole ofapoptosis in erosive and reticular oral lichen planus exhibiting
[28] B K Bloor F K Malik E W Odell and P R MorganldquoQuantitative assessment of apoptosis in oral lichen planusrdquoOral Surgery OralMedicine Oral Pathology Oral Radiology andEndodontics vol 88 no 2 pp 187ndash195 1999
[29] F A C G D Sousa T C Paradella Y R Carvalho and L EB Rosa ldquoImmunohistochemical expression of PCNA p53 baxand bcl-2 in oral lichen planus and epithelial dysplasiardquo Journalof oral science vol 51 no 1 pp 117ndash121 2009
[30] C Bascones-Ilundain M A Gonzalez-Moles G Esparza-Gomez J A Gil-Montoya and A Bascones-Martınez ldquoImpor-tance of apoptoticmechanisms in inflammatory infiltrate of orallichen planus lesionsrdquo Anticancer Research vol 26 no 1 pp357ndash362 2006
[31] V N Pimentel L S de Matos T C B Soares et al ldquoPerforinand granzyme B involvement in oral lesions of lichen planusand chronic GVHDrdquo Journal of Oral Pathology and Medicinevol 39 no 10 pp 741ndash746 2010
[32] L R Oliveira and S Zucoloto ldquoErythema multiforme minor arevisionrdquoTheAmerican Journal of Infectious Diseases vol 4 no4 pp 224ndash231 2008
[33] E Chrysomali F Lozada-Nur N P Dekker S I Papanicolaouand J A Regezi ldquoApoptosis in oral erythema multiformerdquo OralSurgery Oral Medicine Oral Pathology Oral Radiology andEndodontics vol 83 no 2 pp 272ndash280 1997
[34] R Abe T Shimizu A Shibaki H Nakamura HWatanabe andH Shimizu ldquoToxic epidermal necrolysis and Stevens-Johnsonsyndrome are induced by soluble fas ligandrdquo The AmericanJournal of Pathology vol 162 no 5 pp 1515ndash1520 2003
[35] S Inachi H Mizutani and M Shimizu ldquoEpidermal apop-totic cell death in erythema multiforme and Stevens-Johnsonsyndrome contribution of perforin-positive cell infiltrationrdquoArchives of Dermatology vol 133 no 7 pp 845ndash849 1997
[36] A K Vaishnaw E Toubi S Ohsako et al ldquoThe spectrumof apoptotic defects and clinical manifestations includingsystemic lupus erythematosus in humans with Cd95 (FasApo-1)mutationsrdquoArthritis and Rheumatism vol 42 no 9 pp 1833ndash1842 1999
[37] S White and A Rosen ldquoApoptosis in systemic lupus erythe-matosusrdquo Current Opinion in Rheumatology vol 15 no 5 pp557ndash562 2003
[38] D Shah S Sah and S K Nath ldquoInteraction between glu-tathione and apoptosis in systemic lupus erythematosusrdquoAutoimmunity Reviews vol 12 no 7 pp 741ndash751 2013
[39] S Rajagopalan E C Somers R D Brook et al ldquoEndothelial cellapoptosis in systemic lupus erythematosus a common pathwayfor abnormal vascular function and thrombosis propensityrdquoBlood vol 103 no 10 pp 3677ndash3683 2004
[40] M Bektas P Jolly and D S Rubenstein ldquoApoptotic pathwaysin pemphigusrdquo Dermatology Research and Practice vol 2010Article ID 456841 2010
[41] M Puviani A Marconi E Cozzani and C Pincelli ldquoFas ligandin pemphigus sera induces keratinocyte apoptosis through theactivation of caspase-8rdquo Journal of Investigative Dermatologyvol 120 no 1 pp 164ndash167 2003
[42] B H Roh K U Whang M K Cho Y L Park J S Lee andCW Lee ldquoA study of apoptosis in pemphigus vulgarisrdquo KoreanJournal of Dermatology vol 45 no 7 pp 650ndash658 2007
[43] P Deyhimi and P Tavakoli ldquoStudy of apoptosis in oral pem-phigus vulgaris using immunohistochemical marker Bax and
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TUNEL techniquerdquo Journal of Oral Pathology andMedicine vol42 no 5 pp 409ndash414 2013
[44] B Pelacho C Natal A Espana I Sanchez-Carpintero MJ Iraburu and M J Lopez-Zabalza ldquoPemphigus vulgarisautoantibodies induce apoptosis inHaCaT keratinocytesrdquo FEBSLetters vol 566 no 1ndash3 pp 6ndash10 2004
[45] K Yoneda T Furukawa Y-J Zheng et al ldquoAn autocrineparacrine loop linking keratin 14 aggregates to tumor necrosisdactor 120572-mediated cytotoxicity in a keratinocyte model ofepidermolysis bullosa simplexrdquo Journal of Biological Chemistryvol 279 no 8 pp 7296ndash7303 2004
[46] P P Sedghizadeh C M Allen K E Anderson D H Kim JR Kalmar and J C Lang ldquoOral graft-versus-host disease andprogrammed cell death pathogenetic and clinical correlatesrdquoOral Surgery OralMedicine Oral Pathology Oral Radiology andEndodontics vol 97 no 4 pp 491ndash498 2004
[47] T A Graubert J H Russell and T J Ley ldquoThe role of granzymeB in murine models of acute graft-versus-host disease and graftrejectionrdquo Blood vol 87 no 4 pp 1232ndash1237 1996
[48] N Zavazava and D Kabelitz ldquoAlloreactivity and apoptosisin graft rejection and transplantation tolerancerdquo Journal ofLeukocyte Biology vol 68 no 2 pp 167ndash174 2000
[49] A Sarin E KHaddad and PAHenkart ldquoCaspase dependenceof target cell damage induced by cytotoxic lymphocytesrdquo Jour-nal of Immunology vol 161 no 6 pp 2810ndash2816 1998
[50] M Enari H Hug and S Nagata ldquoInvolvement of an ICE-likeprotease in Fas-mediated apoptosisrdquo Nature vol 375 no 6526pp 78ndash81 1995
[51] T H Holmstrom and J E Eriksson ldquoPhophorylation basedsignaling in Fas receptor mediated apoptosisrdquo Critical Reviewsin Immunology vol 20 pp 121ndash152 2000
[52] Y H Yoo A C Gilliam D Whitaker-Menezes R Korngoldand G F Murphy ldquoExperimental induction and ultrastructuralcharacterization of apoptosis in marine acute cutaneous graft-versus-host diseaserdquo Archives of Dermatological Research vol289 no 7 pp 389ndash398 1997
[53] Y Hayashi K Yayagi and N Haneji ldquoInvolvement of apoptoticprotease cascade for tissue destruction in Sjogrenrsquos syndromerdquoArchivum Immunologiae et Therapiae Experimentalis vol 48no 5 pp 399ndash403 2000
[54] A I Bolstad and R Jonsson ldquoThe role of apoptosis in Sjogrenrsquossyndromerdquo Annals of Internal Medicine vol 149 no 1 pp 25ndash29 1998
[55] P Manganelli and P Fietta ldquoApoptosis and Sjogren syndromerdquoSeminars in Arthritis and Rheumatism vol 33 no 1 pp 49ndash652003
[56] M Ohlsson K Skarstein A I Bolstad A C Johannessen andR Jonsson ldquoFas-induced apoptosis is a rare event in Sjogrenrsquossyndromerdquo Laboratory Investigation vol 81 no 1 pp 95ndash1052001
[57] M Sisto S Lisi D Lofrumento M DrsquoAmore P Scagliusiand VMitolo ldquoAutoantibodies from Sjogrenrsquos syndrome triggerapoptosis in salivary gland cell linerdquo Annals of the New YorkAcademy of Sciences vol 1108 pp 418ndash425 2007
[58] L S Young C W Dawson and A G Eliopoulos ldquoViruses andapoptosisrdquo British Medical Bulletin vol 53 no 3 pp 509ndash5211997
[59] B M Polster J Pevsner and J M Hardwick ldquoViral Bcl-2homologs and their role in virus replication and associateddiseasesrdquo Biochimica et Biophysica Acta vol 1644 no 2-3 pp211ndash227 2004
[60] S Cooray ldquoThe pivotal role of phosphatidylinositol 3-kinase-Akt signal transduction in virus survivalrdquo Journal of GeneralVirology vol 85 no 5 pp 1065ndash1076 2004
[61] J G Teodoro andP E Branton ldquoRegulation of apoptosis by viralgene productsrdquo Journal of Virology vol 71 no 3 pp 1739ndash17461997
[62] M L Nguyen and J A Blaho ldquoApoptosis during herpes simplexvirus infectionrdquo Advances in Virus Research vol 69 pp 67ndash972006
[63] A Kather M J Raftery G Devi-Rao et al ldquoHerpes simplexvirus type 1 (HSV-1)-induced apoptosis in human dendriticcells as a result of downregulation of cellular FLICE-inhibitoryprotein and reduced expression of HSV-1 antiapoptotic latency-associated transcript sequencesrdquo Journal of Virology vol 84 no2 pp 1034ndash1046 2010
[64] L Aurelian ldquoHSV-induced apoptosis in herpes encephalitisrdquoCurrent Topics in Microbiology and Immunology vol 289 pp79ndash111 2005
[65] J Ennaciri J Menezes F Proulx and B J Toledano ldquoInductionof apoptosis by herpes simplex virus-1 in neonatal but not adultneutrophilsrdquo Pediatric Research vol 59 no 1 pp 7ndash12 2006
[66] A M Fuentes-Gonzalez A Contreras-Paredes J Manzo-Merino and M Lizano ldquoThe modulation of apoptosis byoncogenic virusesrdquo Virology Journal vol 10 article 182 2013
[67] MThomas and L Banks ldquoInhibition of Bak-induced apoptosisby HPV-18 E6rdquo Oncogene vol 17 no 23 pp 2943ndash2954 1998
[68] M Roshal Y Zhu and V Planelles ldquoApoptosis in AIDSrdquoApoptosis vol 6 no 1-2 pp 103ndash116 2001
[69] N W Cummins and A D Badley ldquoMechanisms of HIV-associated lymphocyte apoptosis 2010rdquo Cell Death and Diseasevol 1 no 11 article e99 2010
[70] A M Loyola S V Cardoso G S Lisa et al ldquoApoptosis inepithelial cells of apical radicular cystsrdquo International Endodon-tic Journal vol 38 no 7 pp 465ndash469 2005
[71] T Suzuki H Kumamoto K Kunimori andKOoya ldquoImmuno-histochemical analysis of apoptosis-related factors in liningepithelium of radicular cystsrdquo Journal of Oral Pathology andMedicine vol 34 no 1 pp 46ndash52 2005
[72] C A Martins E R C Rivero R M Dufloth C P Figueiredoand D S C Vieira ldquoImmunohistochemical detection of factorsrelated to cellular proliferation and apoptosis in radicular anddentigerous cystsrdquo Journal of Endodontics vol 37 no 1 pp 36ndash39 2011
[73] E Kichi Y Enokiya T Muramatsu et al ldquoCell proliferationapoptosis and apoptosis-related factors in odontogenic kerato-cysts and in dentigerous cystsrdquo Journal of Oral Pathology andMedicine vol 34 no 5 pp 280ndash286 2005
[74] A Piattelli M Fioroni and C Rubini ldquoDifferentiation ofodontogenic keratocysts from other odontogenic cysts by theexpression of bcl-2 immunoreactivityrdquo Oral Oncology vol 34no 5 pp 404ndash407 1998
[75] G C P Mateus G H D S P Lanza P H R deMoura H A deMarigo and M C R Horta ldquoCell proliferation and apoptosisin keratocystic odontogenic tumorsrdquo Medicina Oral PatologiaOral y Cirugia Bucal vol 13 no 11 pp E697ndashE702 2008
[76] L Artese A Piattelli C Rubini et al ldquop16 expression inodontogenic tumorsrdquo Tumori vol 94 no 5 pp 718ndash723 2008
[77] L Lo Muzio S Staibano G Pannone et al ldquoExpression of cellcycle and apoptosis-related proteins in sporadic odontogenickeratocysts and odontogenic keratocysts associated with thenevoid basal cell carcinoma syndromerdquo Journal of DentalResearch vol 78 no 7 pp 1345ndash1353 1999
10 Journal of Oral Diseases
[78] D K Kim S G Ahn J Kim and J H Yoon ldquoComparativeKi-67 expression and apoptosis in the odontogenic keratocystassociated with or without an impacted tooth in addition tounilocular and multilocular varietiesrdquo Yonsei Medical Journalvol 44 no 5 pp 841ndash846 2003
[79] M Andric B Dozic B Popovic et al ldquoSurvivin expression inodontogenic keratocysts and correlation with cytomegalovirusinfectionrdquo Oral Diseases vol 16 no 2 pp 156ndash159 2010
[80] I R H Kramer J J Pindborg and M ShearWHOHistologicalTyping of Odontogenic Tumours Springer Berlin Germany1992
[81] H Kumamoto and K Ooya ldquoDetection of mitochondria-mediated apoptosis signaling molecules in ameloblastomasrdquoJournal of Oral Pathology and Medicine vol 34 no 9 pp 565ndash572 2005
[82] H Kumamoto and K Ooya ldquoImmunohistochemical detectionof BH3-only proteins in ameloblastic tumorsrdquo Oral Diseasesvol 14 no 6 pp 550ndash555 2008
[83] H Kumamoto and K Ooya ldquoExpression of tumor necrosisfactor120572 TNF-related apoptosis-inducing ligand and their asso-ciated molecules in ameloblastomasrdquo Journal of Oral Pathologyand Medicine vol 34 no 5 pp 287ndash294 2005
[84] H Kumamoto K Kimi and K Ooya ldquoImmunohistochemicalanalysis of apoptosis-related factors (Fas Fas ligand caspase-3and single-stranded DNA) in ameloblastomasrdquo Journal of OralPathology and Medicine vol 30 no 10 pp 596ndash602 2001
[85] T E Carneiro S A Marinho F D Verli A T M Mesquita NL Lima and J L Miranda ldquoOral squamous papilloma clinicalhistologic and immunohistochemical analysesrdquo Journal of oralscience vol 51 no 3 pp 367ndash372 2009
[86] T Yamaguchi M Shindoh A Amemiya et al ldquoDetectionof human papillomavirus type 2 related sequence in oralpapillomardquo Analytical Cellular Pathology vol 16 no 3 pp 125ndash130 1998
[87] J H Main and M Pavone ldquoActinic cheilitis and carcinoma ofthe liprdquo Journal of Canadian Dental Association vol 60 no 2pp 113ndash116 1994
[88] A Martınez U Brethauer I G Rojas et al ldquoExpression ofapoptotic and cell proliferation regulatory proteins in actiniccheilitisrdquo Journal of Oral Pathology and Medicine vol 34 no5 pp 257ndash262 2005
[89] M A Birchall C MWinterford D J Allan and B V HarmonldquoApoptosis in normal epithelium premalignant and malignantlesions of the oropharynx and oral cavity a preliminary studyrdquoEuropean Journal of Cancer B vol 31 no 6 pp 380ndash383 1995
[90] N Tanda S Mori K Saito K Ikawa and S SakamotoldquoExpression of apoptotic signaling proteins in leukoplakia andoral lichen planus quantitative and topographical studiesrdquoJournal of Oral Pathology and Medicine vol 29 no 8 pp 385ndash393 2000
[91] G Kovesi and B Szende ldquoProgression of the leukoplakia isassociated to changes in apoptotic and mitotic index as well asin p53 and Ki-67 expressionrdquo Oncology vol 46 no 4 pp 333ndash338 2002
[92] H Tsuzuki S Fujieda H Sunaga N Narita M Tokuriki andH Saito ldquoExpression of p27 and apoptosis in oral leukoplakiardquoAnticancer Research vol 23 no 2 pp 1265ndash1270 2003
[93] E Chrysomali J S Greenspan N Dekker D Greenspanand J A Regezi ldquoApoptosis-associated proteins in oral hairyleukoplakiardquo Oral Diseases vol 2 no 4 pp 279ndash284 1996
[94] S H Kaufmann andG J Gores ldquoApoptosis in cancer cause andcurerdquo BioEssays vol 22 pp 1007ndash1017 2000
[95] S Ghavami M Hashemi S R Ande et al ldquoApoptosis andcancer mutations within caspase genesrdquo Journal of MedicalGenetics vol 46 no 8 pp 497ndash510 2009
[96] C M Coutinho-Camillo S V Lourenco I N NishimotoL P Kowalski and F A Soares ldquoCaspase expression in oralsquamous cell carcinomardquo Head and Neck vol 33 no 8 pp1191ndash1198 2011
[97] P J Polverini and J E Nor ldquoApoptosis and predisposition tooral cancerrdquo Critical Reviews in Oral Biology and Medicine vol10 no 2 pp 139ndash152 1999
[98] M Sulkowska W Famulski S Sulkowski et al ldquoCorrelationbetween Bcl-2 protein expression and some clinicopathologicalfeatures of oral squamous cell carcinomardquo Polish Journal ofPathology vol 54 no 1 pp 49ndash52 2003
[99] L L Loro O K Vintermyr P G Liavaag R Jonsson and A CJohannessen ldquoOral squamous cell carcinoma is associated withdecreased bcl-2bax expression ratio and increased apoptosisrdquoHuman Pathology vol 30 no 9 pp 1097ndash1105 1999
[100] M Baltaziak M KodaM Barwijuk-Machała et al ldquoThe role ofBak expression in apoptosis of the oral squamous cell carcinoma(OSCC) and metastases to lymph nodes (LNMs)rdquo AnnalesAcademiae Medicae Bialostocensis vol 49 pp 14ndash15 2004
[101] J C de Vicente L M J Gutierrez A H Zapatero M FF Forcelledo G Hernandez-Vallejo and J S Lopez ArranzldquoPrognostic significance of p53 expression in oral squamous cellcarcinoma without neck node metastasesrdquo Head and Neck vol26 no 1 pp 22ndash30 2004
[102] M A Gonzalez-Moles P Galindo J Gutierrez-Fernandez etal ldquoP53 protein expression in oral squamous cell carcinomasurvival analysisrdquo Anticancer Research vol 21 no 4 pp 2889ndash2894 2001
[103] S Kannan G Jagadeesh Chandran K Raveendran Pillai et alldquoExpression of p53 in leukoplakia and squamous cell carcinomaof the oral mucosa correlation with expression of Ki67rdquo Journalof Clinical Pathology vol 49 no 3 pp M170ndashM175 1996
[104] J Y Koh N P Cho G Kong J D Lee and K Yoon ldquop53mutations and human papillomavirus DNA in oral squamouscell carcinoma correlation with apoptosisrdquo British Journal ofCancer vol 78 no 3 pp 354ndash359 1998
[105] L LoMuzio G Pannone S Staibano et al ldquoSurvivin expressionin oral squamous cell carcinomardquo British Journal of Cancer vol89 no 12 pp 2244ndash2248 2003
[106] Y Jinbu K Tsukinoki N Miyagi et al ldquoExpression of survivinin oral squamous cell carcinomardquo Oral Med Pathol vol 11 pp41ndash44 2006
[107] C Jane A V Nerurkar N V Shirsat R B DeshpandeA D Amrapurkar and F R Karjodkar ldquoIncreased survivinexpression in high-grade oral squamous cell carcinoma a studyin Indian tobacco chewersrdquo Journal of Oral Pathology andMedicine vol 35 no 10 pp 595ndash601 2006
[108] Y-H Kim S-M Kim Y-K Kim S-P Hong M-J Kim andH Myoung ldquoEvaluation of survivin as a prognostic marker inoral squamous cell carcinomardquo Journal of Oral Pathology andMedicine vol 39 no 5 pp 368ndash375 2010
[109] N G Nikitakis J J Sauk and S I Papanicolaou ldquoThe role ofapoptosis in oral disease mechanisms aberrations in neoplas-tic autoimmune infectious hematologic and developmentaldiseases and therapeutic opportunitiesrdquo Oral Surgery OralMedicine Oral Pathology Oral Radiology and Endodontics vol97 no 4 pp 476ndash490 2004
[110] L L Loro O K Vintermyr A C Johannessen P G Liavaagand R Jonsson ldquoSuppression of Fas receptor and negative
Journal of Oral Diseases 11
correlation of Fas ligand with differentiation and apoptosis inoral squamous cell carcinomardquo Journal of Oral Pathology andMedicine vol 28 no 2 pp 82ndash87 1999
[111] N H Al-Rawi H Omer and S Al Kawas ldquoImmunohistochem-ical analysis of P53 and bcl-2 in benign and malignant salivaryglands tumorsrdquo Journal of Oral Pathology and Medicine vol 39no 1 pp 48ndash55 2010
[112] ANordkvist E Roijer G Bang et al ldquoExpression andmutationpatterns of p53 in benign andmalignant salivary gland tumorsrdquoInternational Journal of Oncology vol 16 no 3 pp 477ndash4832000
[113] V J Karja K J Syrjanen A-K Kurvinen and S M SyrjanenldquoExpression and mutations of p53 in salivary gland tumoursrdquoJournal of Oral Pathology and Medicine vol 26 no 5 pp 217ndash223 1997
[114] M Yanezez I Roa M Garcıa G Ibacache and M VillasecaldquoGene Bcl-2 protein expression in salivary gland tumorsrdquoRevista Medica de Chile vol 127 no 2 pp 139ndash142 1999
[115] L Jia R L Esguerra X Tang et al ldquoPrognostic value ofapoptosis and apoptosis-associated proteins in salivary glandadenoid cystic carcinomardquo Pathology International vol 54 no4 pp 217ndash223 2004
[116] Y Soini U Tormanen and P Paakko ldquoApoptosis is inverselyrelated to bcl-2 but not to bax expression in salivary glandtumoursrdquo Histopathology vol 32 no 1 pp 28ndash34 1998
[117] R M Nagler H Kerner S Ben-Eliezer I Minkov and O Ben-Itzhak ldquoPrognostic role of apoptotic Bcl-2 c-erbB-2 and p53tumor markers in salivary gland malignanciesrdquo Oncology vol64 no 4 pp 389ndash398 2003
and central giant cell lesions of the jawsrdquo Tumor Biology vol 32no 5 pp 997ndash1003 2011
[13] J Pammer W Weninger H Hulla P Mazal and R HorvatldquoExpression of regulatory apoptotic proteins in peripheral giantcell granulomas and lesions containing osteoclast-like giantcellsrdquo Journal of Oral Pathology and Medicine vol 27 no 6 pp267ndash271 1998
[14] C Scully and S Porter ldquoOral mucosal disease recurrentaphthous stomatitisrdquo British Journal of Oral and MaxillofacialSurgery vol 46 no 3 pp 198ndash206 2008
[15] T Honma T Saito and Y Fujioka ldquoPossible role of apoptoticcells of the oral epithelium in the pathogenesis of aphthousulcerationrdquoOral Surgery Oral Medicine and Oral Pathology vol59 no 4 pp 379ndash387 1985
[16] J F N Pinto Rodrigues C T Fujiyama Oshima A P RibeiroPaiotti M Franco S S Miki Ihara and D A RibeiroldquoExpression of apoptosis regulatory proteins p53 bcl-2 andbax in recurrent aphthous ulcerationrdquo Journal of the EuropeanAcademy of Dermatology and Venereology vol 26 no 10 pp1247ndash1251 2012
[17] J Gamonal A Bascones A Acevedo E Blanco and A SilvaldquoApoptosis in chronic adult periodontitis analyzed by in situDNA breaks electron microscopy and immunohistochem-istryrdquo Journal of Periodontology vol 72 no 4 pp 517ndash525 2001
[18] F Jarnbring E Somogyi J Dalton A Gustafsson and BKlinge ldquoQuantitative assessment of apoptotic and prolifera-tive gingival keratinocytes in oral and sulcular epithelium inpatients with gingivitis and periodontitisrdquo Journal of ClinicalPeriodontology vol 29 no 12 pp 1065ndash1071 2002
[19] P Kelk A Johansson R Claesson L Hanstrom and S KalfasldquoCaspase 1 involvement in human monocyte lysis induced byActinobacillus actinomycetemcomitans leukotoxinrdquo Infectionand Immunity vol 71 no 8 pp 4448ndash4455 2003
[20] P G Stathopoulou J C Galicia M R Benakanakere C AGarcia J Potempa and D F Kinane ldquoPorphyromonas gingi-valis induce apoptosis in human gingival epithelial cells througha gingipain-dependent mechanismrdquo BMC Microbiology vol 9article 107 2009
[21] T Murata K YaegakiW Qian et al ldquoHydrogen sulfide inducesapoptosis in epithelial cells derived from human gingivalrdquoJournal of Breath Research vol 2 no 1 Article ID 017007 2008
[22] J C Galicia M R Benakanakere P G Stathopoulou and DF Kinane ldquoNeutrophils rescue gingival epithelial cells frombacterial-induced apoptosisrdquo Journal of Leukocyte Biology vol86 no 1 pp 181ndash186 2009
[23] A Kantarci P Augustin E Firatli et al ldquoApoptosis in gingivalovergrowth tissuesrdquo Journal of Dental Research vol 86 no 9pp 888ndash892 2007
[24] VAMurrah andE PGilchrist ldquoAssessment of apoptosis in orallichen planusrdquoOral Surgery OralMedicine Oral Pathology OralRadiology and Endodontics vol 82 no 2 pp 209ndash210 1996
[25] M R Roopashree R V Gondhalekar M C Shashikanth JGeorge S H Thippeswamy and A Shukla ldquoPathogenesis oforal lichen planus a reviewrdquo Journal of Oral Pathology andMedicine vol 39 no 10 pp 729ndash734 2010
[26] R Mattila and S Syrjanen ldquoCaspase cascade pathways inapoptosis of oral lichen planusrdquo Oral Surgery Oral MedicineOral Pathology Oral Radiology and Endodontology vol 110 no5 pp 618ndash623 2010
[27] J M C Brant A C Vasconcelos and L V Rodrigues ldquoRole ofapoptosis in erosive and reticular oral lichen planus exhibiting
[28] B K Bloor F K Malik E W Odell and P R MorganldquoQuantitative assessment of apoptosis in oral lichen planusrdquoOral Surgery OralMedicine Oral Pathology Oral Radiology andEndodontics vol 88 no 2 pp 187ndash195 1999
[29] F A C G D Sousa T C Paradella Y R Carvalho and L EB Rosa ldquoImmunohistochemical expression of PCNA p53 baxand bcl-2 in oral lichen planus and epithelial dysplasiardquo Journalof oral science vol 51 no 1 pp 117ndash121 2009
[30] C Bascones-Ilundain M A Gonzalez-Moles G Esparza-Gomez J A Gil-Montoya and A Bascones-Martınez ldquoImpor-tance of apoptoticmechanisms in inflammatory infiltrate of orallichen planus lesionsrdquo Anticancer Research vol 26 no 1 pp357ndash362 2006
[31] V N Pimentel L S de Matos T C B Soares et al ldquoPerforinand granzyme B involvement in oral lesions of lichen planusand chronic GVHDrdquo Journal of Oral Pathology and Medicinevol 39 no 10 pp 741ndash746 2010
[32] L R Oliveira and S Zucoloto ldquoErythema multiforme minor arevisionrdquoTheAmerican Journal of Infectious Diseases vol 4 no4 pp 224ndash231 2008
[33] E Chrysomali F Lozada-Nur N P Dekker S I Papanicolaouand J A Regezi ldquoApoptosis in oral erythema multiformerdquo OralSurgery Oral Medicine Oral Pathology Oral Radiology andEndodontics vol 83 no 2 pp 272ndash280 1997
[34] R Abe T Shimizu A Shibaki H Nakamura HWatanabe andH Shimizu ldquoToxic epidermal necrolysis and Stevens-Johnsonsyndrome are induced by soluble fas ligandrdquo The AmericanJournal of Pathology vol 162 no 5 pp 1515ndash1520 2003
[35] S Inachi H Mizutani and M Shimizu ldquoEpidermal apop-totic cell death in erythema multiforme and Stevens-Johnsonsyndrome contribution of perforin-positive cell infiltrationrdquoArchives of Dermatology vol 133 no 7 pp 845ndash849 1997
[36] A K Vaishnaw E Toubi S Ohsako et al ldquoThe spectrumof apoptotic defects and clinical manifestations includingsystemic lupus erythematosus in humans with Cd95 (FasApo-1)mutationsrdquoArthritis and Rheumatism vol 42 no 9 pp 1833ndash1842 1999
[37] S White and A Rosen ldquoApoptosis in systemic lupus erythe-matosusrdquo Current Opinion in Rheumatology vol 15 no 5 pp557ndash562 2003
[38] D Shah S Sah and S K Nath ldquoInteraction between glu-tathione and apoptosis in systemic lupus erythematosusrdquoAutoimmunity Reviews vol 12 no 7 pp 741ndash751 2013
[39] S Rajagopalan E C Somers R D Brook et al ldquoEndothelial cellapoptosis in systemic lupus erythematosus a common pathwayfor abnormal vascular function and thrombosis propensityrdquoBlood vol 103 no 10 pp 3677ndash3683 2004
[40] M Bektas P Jolly and D S Rubenstein ldquoApoptotic pathwaysin pemphigusrdquo Dermatology Research and Practice vol 2010Article ID 456841 2010
[41] M Puviani A Marconi E Cozzani and C Pincelli ldquoFas ligandin pemphigus sera induces keratinocyte apoptosis through theactivation of caspase-8rdquo Journal of Investigative Dermatologyvol 120 no 1 pp 164ndash167 2003
[42] B H Roh K U Whang M K Cho Y L Park J S Lee andCW Lee ldquoA study of apoptosis in pemphigus vulgarisrdquo KoreanJournal of Dermatology vol 45 no 7 pp 650ndash658 2007
[43] P Deyhimi and P Tavakoli ldquoStudy of apoptosis in oral pem-phigus vulgaris using immunohistochemical marker Bax and
Journal of Oral Diseases 9
TUNEL techniquerdquo Journal of Oral Pathology andMedicine vol42 no 5 pp 409ndash414 2013
[44] B Pelacho C Natal A Espana I Sanchez-Carpintero MJ Iraburu and M J Lopez-Zabalza ldquoPemphigus vulgarisautoantibodies induce apoptosis inHaCaT keratinocytesrdquo FEBSLetters vol 566 no 1ndash3 pp 6ndash10 2004
[45] K Yoneda T Furukawa Y-J Zheng et al ldquoAn autocrineparacrine loop linking keratin 14 aggregates to tumor necrosisdactor 120572-mediated cytotoxicity in a keratinocyte model ofepidermolysis bullosa simplexrdquo Journal of Biological Chemistryvol 279 no 8 pp 7296ndash7303 2004
[46] P P Sedghizadeh C M Allen K E Anderson D H Kim JR Kalmar and J C Lang ldquoOral graft-versus-host disease andprogrammed cell death pathogenetic and clinical correlatesrdquoOral Surgery OralMedicine Oral Pathology Oral Radiology andEndodontics vol 97 no 4 pp 491ndash498 2004
[47] T A Graubert J H Russell and T J Ley ldquoThe role of granzymeB in murine models of acute graft-versus-host disease and graftrejectionrdquo Blood vol 87 no 4 pp 1232ndash1237 1996
[48] N Zavazava and D Kabelitz ldquoAlloreactivity and apoptosisin graft rejection and transplantation tolerancerdquo Journal ofLeukocyte Biology vol 68 no 2 pp 167ndash174 2000
[49] A Sarin E KHaddad and PAHenkart ldquoCaspase dependenceof target cell damage induced by cytotoxic lymphocytesrdquo Jour-nal of Immunology vol 161 no 6 pp 2810ndash2816 1998
[50] M Enari H Hug and S Nagata ldquoInvolvement of an ICE-likeprotease in Fas-mediated apoptosisrdquo Nature vol 375 no 6526pp 78ndash81 1995
[51] T H Holmstrom and J E Eriksson ldquoPhophorylation basedsignaling in Fas receptor mediated apoptosisrdquo Critical Reviewsin Immunology vol 20 pp 121ndash152 2000
[52] Y H Yoo A C Gilliam D Whitaker-Menezes R Korngoldand G F Murphy ldquoExperimental induction and ultrastructuralcharacterization of apoptosis in marine acute cutaneous graft-versus-host diseaserdquo Archives of Dermatological Research vol289 no 7 pp 389ndash398 1997
[53] Y Hayashi K Yayagi and N Haneji ldquoInvolvement of apoptoticprotease cascade for tissue destruction in Sjogrenrsquos syndromerdquoArchivum Immunologiae et Therapiae Experimentalis vol 48no 5 pp 399ndash403 2000
[54] A I Bolstad and R Jonsson ldquoThe role of apoptosis in Sjogrenrsquossyndromerdquo Annals of Internal Medicine vol 149 no 1 pp 25ndash29 1998
[55] P Manganelli and P Fietta ldquoApoptosis and Sjogren syndromerdquoSeminars in Arthritis and Rheumatism vol 33 no 1 pp 49ndash652003
[56] M Ohlsson K Skarstein A I Bolstad A C Johannessen andR Jonsson ldquoFas-induced apoptosis is a rare event in Sjogrenrsquossyndromerdquo Laboratory Investigation vol 81 no 1 pp 95ndash1052001
[57] M Sisto S Lisi D Lofrumento M DrsquoAmore P Scagliusiand VMitolo ldquoAutoantibodies from Sjogrenrsquos syndrome triggerapoptosis in salivary gland cell linerdquo Annals of the New YorkAcademy of Sciences vol 1108 pp 418ndash425 2007
[58] L S Young C W Dawson and A G Eliopoulos ldquoViruses andapoptosisrdquo British Medical Bulletin vol 53 no 3 pp 509ndash5211997
[59] B M Polster J Pevsner and J M Hardwick ldquoViral Bcl-2homologs and their role in virus replication and associateddiseasesrdquo Biochimica et Biophysica Acta vol 1644 no 2-3 pp211ndash227 2004
[60] S Cooray ldquoThe pivotal role of phosphatidylinositol 3-kinase-Akt signal transduction in virus survivalrdquo Journal of GeneralVirology vol 85 no 5 pp 1065ndash1076 2004
[61] J G Teodoro andP E Branton ldquoRegulation of apoptosis by viralgene productsrdquo Journal of Virology vol 71 no 3 pp 1739ndash17461997
[62] M L Nguyen and J A Blaho ldquoApoptosis during herpes simplexvirus infectionrdquo Advances in Virus Research vol 69 pp 67ndash972006
[63] A Kather M J Raftery G Devi-Rao et al ldquoHerpes simplexvirus type 1 (HSV-1)-induced apoptosis in human dendriticcells as a result of downregulation of cellular FLICE-inhibitoryprotein and reduced expression of HSV-1 antiapoptotic latency-associated transcript sequencesrdquo Journal of Virology vol 84 no2 pp 1034ndash1046 2010
[64] L Aurelian ldquoHSV-induced apoptosis in herpes encephalitisrdquoCurrent Topics in Microbiology and Immunology vol 289 pp79ndash111 2005
[65] J Ennaciri J Menezes F Proulx and B J Toledano ldquoInductionof apoptosis by herpes simplex virus-1 in neonatal but not adultneutrophilsrdquo Pediatric Research vol 59 no 1 pp 7ndash12 2006
[66] A M Fuentes-Gonzalez A Contreras-Paredes J Manzo-Merino and M Lizano ldquoThe modulation of apoptosis byoncogenic virusesrdquo Virology Journal vol 10 article 182 2013
[67] MThomas and L Banks ldquoInhibition of Bak-induced apoptosisby HPV-18 E6rdquo Oncogene vol 17 no 23 pp 2943ndash2954 1998
[68] M Roshal Y Zhu and V Planelles ldquoApoptosis in AIDSrdquoApoptosis vol 6 no 1-2 pp 103ndash116 2001
[69] N W Cummins and A D Badley ldquoMechanisms of HIV-associated lymphocyte apoptosis 2010rdquo Cell Death and Diseasevol 1 no 11 article e99 2010
[70] A M Loyola S V Cardoso G S Lisa et al ldquoApoptosis inepithelial cells of apical radicular cystsrdquo International Endodon-tic Journal vol 38 no 7 pp 465ndash469 2005
[71] T Suzuki H Kumamoto K Kunimori andKOoya ldquoImmuno-histochemical analysis of apoptosis-related factors in liningepithelium of radicular cystsrdquo Journal of Oral Pathology andMedicine vol 34 no 1 pp 46ndash52 2005
[72] C A Martins E R C Rivero R M Dufloth C P Figueiredoand D S C Vieira ldquoImmunohistochemical detection of factorsrelated to cellular proliferation and apoptosis in radicular anddentigerous cystsrdquo Journal of Endodontics vol 37 no 1 pp 36ndash39 2011
[73] E Kichi Y Enokiya T Muramatsu et al ldquoCell proliferationapoptosis and apoptosis-related factors in odontogenic kerato-cysts and in dentigerous cystsrdquo Journal of Oral Pathology andMedicine vol 34 no 5 pp 280ndash286 2005
[74] A Piattelli M Fioroni and C Rubini ldquoDifferentiation ofodontogenic keratocysts from other odontogenic cysts by theexpression of bcl-2 immunoreactivityrdquo Oral Oncology vol 34no 5 pp 404ndash407 1998
[75] G C P Mateus G H D S P Lanza P H R deMoura H A deMarigo and M C R Horta ldquoCell proliferation and apoptosisin keratocystic odontogenic tumorsrdquo Medicina Oral PatologiaOral y Cirugia Bucal vol 13 no 11 pp E697ndashE702 2008
[76] L Artese A Piattelli C Rubini et al ldquop16 expression inodontogenic tumorsrdquo Tumori vol 94 no 5 pp 718ndash723 2008
[77] L Lo Muzio S Staibano G Pannone et al ldquoExpression of cellcycle and apoptosis-related proteins in sporadic odontogenickeratocysts and odontogenic keratocysts associated with thenevoid basal cell carcinoma syndromerdquo Journal of DentalResearch vol 78 no 7 pp 1345ndash1353 1999
10 Journal of Oral Diseases
[78] D K Kim S G Ahn J Kim and J H Yoon ldquoComparativeKi-67 expression and apoptosis in the odontogenic keratocystassociated with or without an impacted tooth in addition tounilocular and multilocular varietiesrdquo Yonsei Medical Journalvol 44 no 5 pp 841ndash846 2003
[79] M Andric B Dozic B Popovic et al ldquoSurvivin expression inodontogenic keratocysts and correlation with cytomegalovirusinfectionrdquo Oral Diseases vol 16 no 2 pp 156ndash159 2010
[80] I R H Kramer J J Pindborg and M ShearWHOHistologicalTyping of Odontogenic Tumours Springer Berlin Germany1992
[81] H Kumamoto and K Ooya ldquoDetection of mitochondria-mediated apoptosis signaling molecules in ameloblastomasrdquoJournal of Oral Pathology and Medicine vol 34 no 9 pp 565ndash572 2005
[82] H Kumamoto and K Ooya ldquoImmunohistochemical detectionof BH3-only proteins in ameloblastic tumorsrdquo Oral Diseasesvol 14 no 6 pp 550ndash555 2008
[83] H Kumamoto and K Ooya ldquoExpression of tumor necrosisfactor120572 TNF-related apoptosis-inducing ligand and their asso-ciated molecules in ameloblastomasrdquo Journal of Oral Pathologyand Medicine vol 34 no 5 pp 287ndash294 2005
[84] H Kumamoto K Kimi and K Ooya ldquoImmunohistochemicalanalysis of apoptosis-related factors (Fas Fas ligand caspase-3and single-stranded DNA) in ameloblastomasrdquo Journal of OralPathology and Medicine vol 30 no 10 pp 596ndash602 2001
[85] T E Carneiro S A Marinho F D Verli A T M Mesquita NL Lima and J L Miranda ldquoOral squamous papilloma clinicalhistologic and immunohistochemical analysesrdquo Journal of oralscience vol 51 no 3 pp 367ndash372 2009
[86] T Yamaguchi M Shindoh A Amemiya et al ldquoDetectionof human papillomavirus type 2 related sequence in oralpapillomardquo Analytical Cellular Pathology vol 16 no 3 pp 125ndash130 1998
[87] J H Main and M Pavone ldquoActinic cheilitis and carcinoma ofthe liprdquo Journal of Canadian Dental Association vol 60 no 2pp 113ndash116 1994
[88] A Martınez U Brethauer I G Rojas et al ldquoExpression ofapoptotic and cell proliferation regulatory proteins in actiniccheilitisrdquo Journal of Oral Pathology and Medicine vol 34 no5 pp 257ndash262 2005
[89] M A Birchall C MWinterford D J Allan and B V HarmonldquoApoptosis in normal epithelium premalignant and malignantlesions of the oropharynx and oral cavity a preliminary studyrdquoEuropean Journal of Cancer B vol 31 no 6 pp 380ndash383 1995
[90] N Tanda S Mori K Saito K Ikawa and S SakamotoldquoExpression of apoptotic signaling proteins in leukoplakia andoral lichen planus quantitative and topographical studiesrdquoJournal of Oral Pathology and Medicine vol 29 no 8 pp 385ndash393 2000
[91] G Kovesi and B Szende ldquoProgression of the leukoplakia isassociated to changes in apoptotic and mitotic index as well asin p53 and Ki-67 expressionrdquo Oncology vol 46 no 4 pp 333ndash338 2002
[92] H Tsuzuki S Fujieda H Sunaga N Narita M Tokuriki andH Saito ldquoExpression of p27 and apoptosis in oral leukoplakiardquoAnticancer Research vol 23 no 2 pp 1265ndash1270 2003
[93] E Chrysomali J S Greenspan N Dekker D Greenspanand J A Regezi ldquoApoptosis-associated proteins in oral hairyleukoplakiardquo Oral Diseases vol 2 no 4 pp 279ndash284 1996
[94] S H Kaufmann andG J Gores ldquoApoptosis in cancer cause andcurerdquo BioEssays vol 22 pp 1007ndash1017 2000
[95] S Ghavami M Hashemi S R Ande et al ldquoApoptosis andcancer mutations within caspase genesrdquo Journal of MedicalGenetics vol 46 no 8 pp 497ndash510 2009
[96] C M Coutinho-Camillo S V Lourenco I N NishimotoL P Kowalski and F A Soares ldquoCaspase expression in oralsquamous cell carcinomardquo Head and Neck vol 33 no 8 pp1191ndash1198 2011
[97] P J Polverini and J E Nor ldquoApoptosis and predisposition tooral cancerrdquo Critical Reviews in Oral Biology and Medicine vol10 no 2 pp 139ndash152 1999
[98] M Sulkowska W Famulski S Sulkowski et al ldquoCorrelationbetween Bcl-2 protein expression and some clinicopathologicalfeatures of oral squamous cell carcinomardquo Polish Journal ofPathology vol 54 no 1 pp 49ndash52 2003
[99] L L Loro O K Vintermyr P G Liavaag R Jonsson and A CJohannessen ldquoOral squamous cell carcinoma is associated withdecreased bcl-2bax expression ratio and increased apoptosisrdquoHuman Pathology vol 30 no 9 pp 1097ndash1105 1999
[100] M Baltaziak M KodaM Barwijuk-Machała et al ldquoThe role ofBak expression in apoptosis of the oral squamous cell carcinoma(OSCC) and metastases to lymph nodes (LNMs)rdquo AnnalesAcademiae Medicae Bialostocensis vol 49 pp 14ndash15 2004
[101] J C de Vicente L M J Gutierrez A H Zapatero M FF Forcelledo G Hernandez-Vallejo and J S Lopez ArranzldquoPrognostic significance of p53 expression in oral squamous cellcarcinoma without neck node metastasesrdquo Head and Neck vol26 no 1 pp 22ndash30 2004
[102] M A Gonzalez-Moles P Galindo J Gutierrez-Fernandez etal ldquoP53 protein expression in oral squamous cell carcinomasurvival analysisrdquo Anticancer Research vol 21 no 4 pp 2889ndash2894 2001
[103] S Kannan G Jagadeesh Chandran K Raveendran Pillai et alldquoExpression of p53 in leukoplakia and squamous cell carcinomaof the oral mucosa correlation with expression of Ki67rdquo Journalof Clinical Pathology vol 49 no 3 pp M170ndashM175 1996
[104] J Y Koh N P Cho G Kong J D Lee and K Yoon ldquop53mutations and human papillomavirus DNA in oral squamouscell carcinoma correlation with apoptosisrdquo British Journal ofCancer vol 78 no 3 pp 354ndash359 1998
[105] L LoMuzio G Pannone S Staibano et al ldquoSurvivin expressionin oral squamous cell carcinomardquo British Journal of Cancer vol89 no 12 pp 2244ndash2248 2003
[106] Y Jinbu K Tsukinoki N Miyagi et al ldquoExpression of survivinin oral squamous cell carcinomardquo Oral Med Pathol vol 11 pp41ndash44 2006
[107] C Jane A V Nerurkar N V Shirsat R B DeshpandeA D Amrapurkar and F R Karjodkar ldquoIncreased survivinexpression in high-grade oral squamous cell carcinoma a studyin Indian tobacco chewersrdquo Journal of Oral Pathology andMedicine vol 35 no 10 pp 595ndash601 2006
[108] Y-H Kim S-M Kim Y-K Kim S-P Hong M-J Kim andH Myoung ldquoEvaluation of survivin as a prognostic marker inoral squamous cell carcinomardquo Journal of Oral Pathology andMedicine vol 39 no 5 pp 368ndash375 2010
[109] N G Nikitakis J J Sauk and S I Papanicolaou ldquoThe role ofapoptosis in oral disease mechanisms aberrations in neoplas-tic autoimmune infectious hematologic and developmentaldiseases and therapeutic opportunitiesrdquo Oral Surgery OralMedicine Oral Pathology Oral Radiology and Endodontics vol97 no 4 pp 476ndash490 2004
[110] L L Loro O K Vintermyr A C Johannessen P G Liavaagand R Jonsson ldquoSuppression of Fas receptor and negative
Journal of Oral Diseases 11
correlation of Fas ligand with differentiation and apoptosis inoral squamous cell carcinomardquo Journal of Oral Pathology andMedicine vol 28 no 2 pp 82ndash87 1999
[111] N H Al-Rawi H Omer and S Al Kawas ldquoImmunohistochem-ical analysis of P53 and bcl-2 in benign and malignant salivaryglands tumorsrdquo Journal of Oral Pathology and Medicine vol 39no 1 pp 48ndash55 2010
[112] ANordkvist E Roijer G Bang et al ldquoExpression andmutationpatterns of p53 in benign andmalignant salivary gland tumorsrdquoInternational Journal of Oncology vol 16 no 3 pp 477ndash4832000
[113] V J Karja K J Syrjanen A-K Kurvinen and S M SyrjanenldquoExpression and mutations of p53 in salivary gland tumoursrdquoJournal of Oral Pathology and Medicine vol 26 no 5 pp 217ndash223 1997
[114] M Yanezez I Roa M Garcıa G Ibacache and M VillasecaldquoGene Bcl-2 protein expression in salivary gland tumorsrdquoRevista Medica de Chile vol 127 no 2 pp 139ndash142 1999
[115] L Jia R L Esguerra X Tang et al ldquoPrognostic value ofapoptosis and apoptosis-associated proteins in salivary glandadenoid cystic carcinomardquo Pathology International vol 54 no4 pp 217ndash223 2004
[116] Y Soini U Tormanen and P Paakko ldquoApoptosis is inverselyrelated to bcl-2 but not to bax expression in salivary glandtumoursrdquo Histopathology vol 32 no 1 pp 28ndash34 1998
[117] R M Nagler H Kerner S Ben-Eliezer I Minkov and O Ben-Itzhak ldquoPrognostic role of apoptotic Bcl-2 c-erbB-2 and p53tumor markers in salivary gland malignanciesrdquo Oncology vol64 no 4 pp 389ndash398 2003
TUNEL techniquerdquo Journal of Oral Pathology andMedicine vol42 no 5 pp 409ndash414 2013
[44] B Pelacho C Natal A Espana I Sanchez-Carpintero MJ Iraburu and M J Lopez-Zabalza ldquoPemphigus vulgarisautoantibodies induce apoptosis inHaCaT keratinocytesrdquo FEBSLetters vol 566 no 1ndash3 pp 6ndash10 2004
[45] K Yoneda T Furukawa Y-J Zheng et al ldquoAn autocrineparacrine loop linking keratin 14 aggregates to tumor necrosisdactor 120572-mediated cytotoxicity in a keratinocyte model ofepidermolysis bullosa simplexrdquo Journal of Biological Chemistryvol 279 no 8 pp 7296ndash7303 2004
[46] P P Sedghizadeh C M Allen K E Anderson D H Kim JR Kalmar and J C Lang ldquoOral graft-versus-host disease andprogrammed cell death pathogenetic and clinical correlatesrdquoOral Surgery OralMedicine Oral Pathology Oral Radiology andEndodontics vol 97 no 4 pp 491ndash498 2004
[47] T A Graubert J H Russell and T J Ley ldquoThe role of granzymeB in murine models of acute graft-versus-host disease and graftrejectionrdquo Blood vol 87 no 4 pp 1232ndash1237 1996
[48] N Zavazava and D Kabelitz ldquoAlloreactivity and apoptosisin graft rejection and transplantation tolerancerdquo Journal ofLeukocyte Biology vol 68 no 2 pp 167ndash174 2000
[49] A Sarin E KHaddad and PAHenkart ldquoCaspase dependenceof target cell damage induced by cytotoxic lymphocytesrdquo Jour-nal of Immunology vol 161 no 6 pp 2810ndash2816 1998
[50] M Enari H Hug and S Nagata ldquoInvolvement of an ICE-likeprotease in Fas-mediated apoptosisrdquo Nature vol 375 no 6526pp 78ndash81 1995
[51] T H Holmstrom and J E Eriksson ldquoPhophorylation basedsignaling in Fas receptor mediated apoptosisrdquo Critical Reviewsin Immunology vol 20 pp 121ndash152 2000
[52] Y H Yoo A C Gilliam D Whitaker-Menezes R Korngoldand G F Murphy ldquoExperimental induction and ultrastructuralcharacterization of apoptosis in marine acute cutaneous graft-versus-host diseaserdquo Archives of Dermatological Research vol289 no 7 pp 389ndash398 1997
[53] Y Hayashi K Yayagi and N Haneji ldquoInvolvement of apoptoticprotease cascade for tissue destruction in Sjogrenrsquos syndromerdquoArchivum Immunologiae et Therapiae Experimentalis vol 48no 5 pp 399ndash403 2000
[54] A I Bolstad and R Jonsson ldquoThe role of apoptosis in Sjogrenrsquossyndromerdquo Annals of Internal Medicine vol 149 no 1 pp 25ndash29 1998
[55] P Manganelli and P Fietta ldquoApoptosis and Sjogren syndromerdquoSeminars in Arthritis and Rheumatism vol 33 no 1 pp 49ndash652003
[56] M Ohlsson K Skarstein A I Bolstad A C Johannessen andR Jonsson ldquoFas-induced apoptosis is a rare event in Sjogrenrsquossyndromerdquo Laboratory Investigation vol 81 no 1 pp 95ndash1052001
[57] M Sisto S Lisi D Lofrumento M DrsquoAmore P Scagliusiand VMitolo ldquoAutoantibodies from Sjogrenrsquos syndrome triggerapoptosis in salivary gland cell linerdquo Annals of the New YorkAcademy of Sciences vol 1108 pp 418ndash425 2007
[58] L S Young C W Dawson and A G Eliopoulos ldquoViruses andapoptosisrdquo British Medical Bulletin vol 53 no 3 pp 509ndash5211997
[59] B M Polster J Pevsner and J M Hardwick ldquoViral Bcl-2homologs and their role in virus replication and associateddiseasesrdquo Biochimica et Biophysica Acta vol 1644 no 2-3 pp211ndash227 2004
[60] S Cooray ldquoThe pivotal role of phosphatidylinositol 3-kinase-Akt signal transduction in virus survivalrdquo Journal of GeneralVirology vol 85 no 5 pp 1065ndash1076 2004
[61] J G Teodoro andP E Branton ldquoRegulation of apoptosis by viralgene productsrdquo Journal of Virology vol 71 no 3 pp 1739ndash17461997
[62] M L Nguyen and J A Blaho ldquoApoptosis during herpes simplexvirus infectionrdquo Advances in Virus Research vol 69 pp 67ndash972006
[63] A Kather M J Raftery G Devi-Rao et al ldquoHerpes simplexvirus type 1 (HSV-1)-induced apoptosis in human dendriticcells as a result of downregulation of cellular FLICE-inhibitoryprotein and reduced expression of HSV-1 antiapoptotic latency-associated transcript sequencesrdquo Journal of Virology vol 84 no2 pp 1034ndash1046 2010
[64] L Aurelian ldquoHSV-induced apoptosis in herpes encephalitisrdquoCurrent Topics in Microbiology and Immunology vol 289 pp79ndash111 2005
[65] J Ennaciri J Menezes F Proulx and B J Toledano ldquoInductionof apoptosis by herpes simplex virus-1 in neonatal but not adultneutrophilsrdquo Pediatric Research vol 59 no 1 pp 7ndash12 2006
[66] A M Fuentes-Gonzalez A Contreras-Paredes J Manzo-Merino and M Lizano ldquoThe modulation of apoptosis byoncogenic virusesrdquo Virology Journal vol 10 article 182 2013
[67] MThomas and L Banks ldquoInhibition of Bak-induced apoptosisby HPV-18 E6rdquo Oncogene vol 17 no 23 pp 2943ndash2954 1998
[68] M Roshal Y Zhu and V Planelles ldquoApoptosis in AIDSrdquoApoptosis vol 6 no 1-2 pp 103ndash116 2001
[69] N W Cummins and A D Badley ldquoMechanisms of HIV-associated lymphocyte apoptosis 2010rdquo Cell Death and Diseasevol 1 no 11 article e99 2010
[70] A M Loyola S V Cardoso G S Lisa et al ldquoApoptosis inepithelial cells of apical radicular cystsrdquo International Endodon-tic Journal vol 38 no 7 pp 465ndash469 2005
[71] T Suzuki H Kumamoto K Kunimori andKOoya ldquoImmuno-histochemical analysis of apoptosis-related factors in liningepithelium of radicular cystsrdquo Journal of Oral Pathology andMedicine vol 34 no 1 pp 46ndash52 2005
[72] C A Martins E R C Rivero R M Dufloth C P Figueiredoand D S C Vieira ldquoImmunohistochemical detection of factorsrelated to cellular proliferation and apoptosis in radicular anddentigerous cystsrdquo Journal of Endodontics vol 37 no 1 pp 36ndash39 2011
[73] E Kichi Y Enokiya T Muramatsu et al ldquoCell proliferationapoptosis and apoptosis-related factors in odontogenic kerato-cysts and in dentigerous cystsrdquo Journal of Oral Pathology andMedicine vol 34 no 5 pp 280ndash286 2005
[74] A Piattelli M Fioroni and C Rubini ldquoDifferentiation ofodontogenic keratocysts from other odontogenic cysts by theexpression of bcl-2 immunoreactivityrdquo Oral Oncology vol 34no 5 pp 404ndash407 1998
[75] G C P Mateus G H D S P Lanza P H R deMoura H A deMarigo and M C R Horta ldquoCell proliferation and apoptosisin keratocystic odontogenic tumorsrdquo Medicina Oral PatologiaOral y Cirugia Bucal vol 13 no 11 pp E697ndashE702 2008
[76] L Artese A Piattelli C Rubini et al ldquop16 expression inodontogenic tumorsrdquo Tumori vol 94 no 5 pp 718ndash723 2008
[77] L Lo Muzio S Staibano G Pannone et al ldquoExpression of cellcycle and apoptosis-related proteins in sporadic odontogenickeratocysts and odontogenic keratocysts associated with thenevoid basal cell carcinoma syndromerdquo Journal of DentalResearch vol 78 no 7 pp 1345ndash1353 1999
10 Journal of Oral Diseases
[78] D K Kim S G Ahn J Kim and J H Yoon ldquoComparativeKi-67 expression and apoptosis in the odontogenic keratocystassociated with or without an impacted tooth in addition tounilocular and multilocular varietiesrdquo Yonsei Medical Journalvol 44 no 5 pp 841ndash846 2003
[79] M Andric B Dozic B Popovic et al ldquoSurvivin expression inodontogenic keratocysts and correlation with cytomegalovirusinfectionrdquo Oral Diseases vol 16 no 2 pp 156ndash159 2010
[80] I R H Kramer J J Pindborg and M ShearWHOHistologicalTyping of Odontogenic Tumours Springer Berlin Germany1992
[81] H Kumamoto and K Ooya ldquoDetection of mitochondria-mediated apoptosis signaling molecules in ameloblastomasrdquoJournal of Oral Pathology and Medicine vol 34 no 9 pp 565ndash572 2005
[82] H Kumamoto and K Ooya ldquoImmunohistochemical detectionof BH3-only proteins in ameloblastic tumorsrdquo Oral Diseasesvol 14 no 6 pp 550ndash555 2008
[83] H Kumamoto and K Ooya ldquoExpression of tumor necrosisfactor120572 TNF-related apoptosis-inducing ligand and their asso-ciated molecules in ameloblastomasrdquo Journal of Oral Pathologyand Medicine vol 34 no 5 pp 287ndash294 2005
[84] H Kumamoto K Kimi and K Ooya ldquoImmunohistochemicalanalysis of apoptosis-related factors (Fas Fas ligand caspase-3and single-stranded DNA) in ameloblastomasrdquo Journal of OralPathology and Medicine vol 30 no 10 pp 596ndash602 2001
[85] T E Carneiro S A Marinho F D Verli A T M Mesquita NL Lima and J L Miranda ldquoOral squamous papilloma clinicalhistologic and immunohistochemical analysesrdquo Journal of oralscience vol 51 no 3 pp 367ndash372 2009
[86] T Yamaguchi M Shindoh A Amemiya et al ldquoDetectionof human papillomavirus type 2 related sequence in oralpapillomardquo Analytical Cellular Pathology vol 16 no 3 pp 125ndash130 1998
[87] J H Main and M Pavone ldquoActinic cheilitis and carcinoma ofthe liprdquo Journal of Canadian Dental Association vol 60 no 2pp 113ndash116 1994
[88] A Martınez U Brethauer I G Rojas et al ldquoExpression ofapoptotic and cell proliferation regulatory proteins in actiniccheilitisrdquo Journal of Oral Pathology and Medicine vol 34 no5 pp 257ndash262 2005
[89] M A Birchall C MWinterford D J Allan and B V HarmonldquoApoptosis in normal epithelium premalignant and malignantlesions of the oropharynx and oral cavity a preliminary studyrdquoEuropean Journal of Cancer B vol 31 no 6 pp 380ndash383 1995
[90] N Tanda S Mori K Saito K Ikawa and S SakamotoldquoExpression of apoptotic signaling proteins in leukoplakia andoral lichen planus quantitative and topographical studiesrdquoJournal of Oral Pathology and Medicine vol 29 no 8 pp 385ndash393 2000
[91] G Kovesi and B Szende ldquoProgression of the leukoplakia isassociated to changes in apoptotic and mitotic index as well asin p53 and Ki-67 expressionrdquo Oncology vol 46 no 4 pp 333ndash338 2002
[92] H Tsuzuki S Fujieda H Sunaga N Narita M Tokuriki andH Saito ldquoExpression of p27 and apoptosis in oral leukoplakiardquoAnticancer Research vol 23 no 2 pp 1265ndash1270 2003
[93] E Chrysomali J S Greenspan N Dekker D Greenspanand J A Regezi ldquoApoptosis-associated proteins in oral hairyleukoplakiardquo Oral Diseases vol 2 no 4 pp 279ndash284 1996
[94] S H Kaufmann andG J Gores ldquoApoptosis in cancer cause andcurerdquo BioEssays vol 22 pp 1007ndash1017 2000
[95] S Ghavami M Hashemi S R Ande et al ldquoApoptosis andcancer mutations within caspase genesrdquo Journal of MedicalGenetics vol 46 no 8 pp 497ndash510 2009
[96] C M Coutinho-Camillo S V Lourenco I N NishimotoL P Kowalski and F A Soares ldquoCaspase expression in oralsquamous cell carcinomardquo Head and Neck vol 33 no 8 pp1191ndash1198 2011
[97] P J Polverini and J E Nor ldquoApoptosis and predisposition tooral cancerrdquo Critical Reviews in Oral Biology and Medicine vol10 no 2 pp 139ndash152 1999
[98] M Sulkowska W Famulski S Sulkowski et al ldquoCorrelationbetween Bcl-2 protein expression and some clinicopathologicalfeatures of oral squamous cell carcinomardquo Polish Journal ofPathology vol 54 no 1 pp 49ndash52 2003
[99] L L Loro O K Vintermyr P G Liavaag R Jonsson and A CJohannessen ldquoOral squamous cell carcinoma is associated withdecreased bcl-2bax expression ratio and increased apoptosisrdquoHuman Pathology vol 30 no 9 pp 1097ndash1105 1999
[100] M Baltaziak M KodaM Barwijuk-Machała et al ldquoThe role ofBak expression in apoptosis of the oral squamous cell carcinoma(OSCC) and metastases to lymph nodes (LNMs)rdquo AnnalesAcademiae Medicae Bialostocensis vol 49 pp 14ndash15 2004
[101] J C de Vicente L M J Gutierrez A H Zapatero M FF Forcelledo G Hernandez-Vallejo and J S Lopez ArranzldquoPrognostic significance of p53 expression in oral squamous cellcarcinoma without neck node metastasesrdquo Head and Neck vol26 no 1 pp 22ndash30 2004
[102] M A Gonzalez-Moles P Galindo J Gutierrez-Fernandez etal ldquoP53 protein expression in oral squamous cell carcinomasurvival analysisrdquo Anticancer Research vol 21 no 4 pp 2889ndash2894 2001
[103] S Kannan G Jagadeesh Chandran K Raveendran Pillai et alldquoExpression of p53 in leukoplakia and squamous cell carcinomaof the oral mucosa correlation with expression of Ki67rdquo Journalof Clinical Pathology vol 49 no 3 pp M170ndashM175 1996
[104] J Y Koh N P Cho G Kong J D Lee and K Yoon ldquop53mutations and human papillomavirus DNA in oral squamouscell carcinoma correlation with apoptosisrdquo British Journal ofCancer vol 78 no 3 pp 354ndash359 1998
[105] L LoMuzio G Pannone S Staibano et al ldquoSurvivin expressionin oral squamous cell carcinomardquo British Journal of Cancer vol89 no 12 pp 2244ndash2248 2003
[106] Y Jinbu K Tsukinoki N Miyagi et al ldquoExpression of survivinin oral squamous cell carcinomardquo Oral Med Pathol vol 11 pp41ndash44 2006
[107] C Jane A V Nerurkar N V Shirsat R B DeshpandeA D Amrapurkar and F R Karjodkar ldquoIncreased survivinexpression in high-grade oral squamous cell carcinoma a studyin Indian tobacco chewersrdquo Journal of Oral Pathology andMedicine vol 35 no 10 pp 595ndash601 2006
[108] Y-H Kim S-M Kim Y-K Kim S-P Hong M-J Kim andH Myoung ldquoEvaluation of survivin as a prognostic marker inoral squamous cell carcinomardquo Journal of Oral Pathology andMedicine vol 39 no 5 pp 368ndash375 2010
[109] N G Nikitakis J J Sauk and S I Papanicolaou ldquoThe role ofapoptosis in oral disease mechanisms aberrations in neoplas-tic autoimmune infectious hematologic and developmentaldiseases and therapeutic opportunitiesrdquo Oral Surgery OralMedicine Oral Pathology Oral Radiology and Endodontics vol97 no 4 pp 476ndash490 2004
[110] L L Loro O K Vintermyr A C Johannessen P G Liavaagand R Jonsson ldquoSuppression of Fas receptor and negative
Journal of Oral Diseases 11
correlation of Fas ligand with differentiation and apoptosis inoral squamous cell carcinomardquo Journal of Oral Pathology andMedicine vol 28 no 2 pp 82ndash87 1999
[111] N H Al-Rawi H Omer and S Al Kawas ldquoImmunohistochem-ical analysis of P53 and bcl-2 in benign and malignant salivaryglands tumorsrdquo Journal of Oral Pathology and Medicine vol 39no 1 pp 48ndash55 2010
[112] ANordkvist E Roijer G Bang et al ldquoExpression andmutationpatterns of p53 in benign andmalignant salivary gland tumorsrdquoInternational Journal of Oncology vol 16 no 3 pp 477ndash4832000
[113] V J Karja K J Syrjanen A-K Kurvinen and S M SyrjanenldquoExpression and mutations of p53 in salivary gland tumoursrdquoJournal of Oral Pathology and Medicine vol 26 no 5 pp 217ndash223 1997
[114] M Yanezez I Roa M Garcıa G Ibacache and M VillasecaldquoGene Bcl-2 protein expression in salivary gland tumorsrdquoRevista Medica de Chile vol 127 no 2 pp 139ndash142 1999
[115] L Jia R L Esguerra X Tang et al ldquoPrognostic value ofapoptosis and apoptosis-associated proteins in salivary glandadenoid cystic carcinomardquo Pathology International vol 54 no4 pp 217ndash223 2004
[116] Y Soini U Tormanen and P Paakko ldquoApoptosis is inverselyrelated to bcl-2 but not to bax expression in salivary glandtumoursrdquo Histopathology vol 32 no 1 pp 28ndash34 1998
[117] R M Nagler H Kerner S Ben-Eliezer I Minkov and O Ben-Itzhak ldquoPrognostic role of apoptotic Bcl-2 c-erbB-2 and p53tumor markers in salivary gland malignanciesrdquo Oncology vol64 no 4 pp 389ndash398 2003
[78] D K Kim S G Ahn J Kim and J H Yoon ldquoComparativeKi-67 expression and apoptosis in the odontogenic keratocystassociated with or without an impacted tooth in addition tounilocular and multilocular varietiesrdquo Yonsei Medical Journalvol 44 no 5 pp 841ndash846 2003
[79] M Andric B Dozic B Popovic et al ldquoSurvivin expression inodontogenic keratocysts and correlation with cytomegalovirusinfectionrdquo Oral Diseases vol 16 no 2 pp 156ndash159 2010
[80] I R H Kramer J J Pindborg and M ShearWHOHistologicalTyping of Odontogenic Tumours Springer Berlin Germany1992
[81] H Kumamoto and K Ooya ldquoDetection of mitochondria-mediated apoptosis signaling molecules in ameloblastomasrdquoJournal of Oral Pathology and Medicine vol 34 no 9 pp 565ndash572 2005
[82] H Kumamoto and K Ooya ldquoImmunohistochemical detectionof BH3-only proteins in ameloblastic tumorsrdquo Oral Diseasesvol 14 no 6 pp 550ndash555 2008
[83] H Kumamoto and K Ooya ldquoExpression of tumor necrosisfactor120572 TNF-related apoptosis-inducing ligand and their asso-ciated molecules in ameloblastomasrdquo Journal of Oral Pathologyand Medicine vol 34 no 5 pp 287ndash294 2005
[84] H Kumamoto K Kimi and K Ooya ldquoImmunohistochemicalanalysis of apoptosis-related factors (Fas Fas ligand caspase-3and single-stranded DNA) in ameloblastomasrdquo Journal of OralPathology and Medicine vol 30 no 10 pp 596ndash602 2001
[85] T E Carneiro S A Marinho F D Verli A T M Mesquita NL Lima and J L Miranda ldquoOral squamous papilloma clinicalhistologic and immunohistochemical analysesrdquo Journal of oralscience vol 51 no 3 pp 367ndash372 2009
[86] T Yamaguchi M Shindoh A Amemiya et al ldquoDetectionof human papillomavirus type 2 related sequence in oralpapillomardquo Analytical Cellular Pathology vol 16 no 3 pp 125ndash130 1998
[87] J H Main and M Pavone ldquoActinic cheilitis and carcinoma ofthe liprdquo Journal of Canadian Dental Association vol 60 no 2pp 113ndash116 1994
[88] A Martınez U Brethauer I G Rojas et al ldquoExpression ofapoptotic and cell proliferation regulatory proteins in actiniccheilitisrdquo Journal of Oral Pathology and Medicine vol 34 no5 pp 257ndash262 2005
[89] M A Birchall C MWinterford D J Allan and B V HarmonldquoApoptosis in normal epithelium premalignant and malignantlesions of the oropharynx and oral cavity a preliminary studyrdquoEuropean Journal of Cancer B vol 31 no 6 pp 380ndash383 1995
[90] N Tanda S Mori K Saito K Ikawa and S SakamotoldquoExpression of apoptotic signaling proteins in leukoplakia andoral lichen planus quantitative and topographical studiesrdquoJournal of Oral Pathology and Medicine vol 29 no 8 pp 385ndash393 2000
[91] G Kovesi and B Szende ldquoProgression of the leukoplakia isassociated to changes in apoptotic and mitotic index as well asin p53 and Ki-67 expressionrdquo Oncology vol 46 no 4 pp 333ndash338 2002
[92] H Tsuzuki S Fujieda H Sunaga N Narita M Tokuriki andH Saito ldquoExpression of p27 and apoptosis in oral leukoplakiardquoAnticancer Research vol 23 no 2 pp 1265ndash1270 2003
[93] E Chrysomali J S Greenspan N Dekker D Greenspanand J A Regezi ldquoApoptosis-associated proteins in oral hairyleukoplakiardquo Oral Diseases vol 2 no 4 pp 279ndash284 1996
[94] S H Kaufmann andG J Gores ldquoApoptosis in cancer cause andcurerdquo BioEssays vol 22 pp 1007ndash1017 2000
[95] S Ghavami M Hashemi S R Ande et al ldquoApoptosis andcancer mutations within caspase genesrdquo Journal of MedicalGenetics vol 46 no 8 pp 497ndash510 2009
[96] C M Coutinho-Camillo S V Lourenco I N NishimotoL P Kowalski and F A Soares ldquoCaspase expression in oralsquamous cell carcinomardquo Head and Neck vol 33 no 8 pp1191ndash1198 2011
[97] P J Polverini and J E Nor ldquoApoptosis and predisposition tooral cancerrdquo Critical Reviews in Oral Biology and Medicine vol10 no 2 pp 139ndash152 1999
[98] M Sulkowska W Famulski S Sulkowski et al ldquoCorrelationbetween Bcl-2 protein expression and some clinicopathologicalfeatures of oral squamous cell carcinomardquo Polish Journal ofPathology vol 54 no 1 pp 49ndash52 2003
[99] L L Loro O K Vintermyr P G Liavaag R Jonsson and A CJohannessen ldquoOral squamous cell carcinoma is associated withdecreased bcl-2bax expression ratio and increased apoptosisrdquoHuman Pathology vol 30 no 9 pp 1097ndash1105 1999
[100] M Baltaziak M KodaM Barwijuk-Machała et al ldquoThe role ofBak expression in apoptosis of the oral squamous cell carcinoma(OSCC) and metastases to lymph nodes (LNMs)rdquo AnnalesAcademiae Medicae Bialostocensis vol 49 pp 14ndash15 2004
[101] J C de Vicente L M J Gutierrez A H Zapatero M FF Forcelledo G Hernandez-Vallejo and J S Lopez ArranzldquoPrognostic significance of p53 expression in oral squamous cellcarcinoma without neck node metastasesrdquo Head and Neck vol26 no 1 pp 22ndash30 2004
[102] M A Gonzalez-Moles P Galindo J Gutierrez-Fernandez etal ldquoP53 protein expression in oral squamous cell carcinomasurvival analysisrdquo Anticancer Research vol 21 no 4 pp 2889ndash2894 2001
[103] S Kannan G Jagadeesh Chandran K Raveendran Pillai et alldquoExpression of p53 in leukoplakia and squamous cell carcinomaof the oral mucosa correlation with expression of Ki67rdquo Journalof Clinical Pathology vol 49 no 3 pp M170ndashM175 1996
[104] J Y Koh N P Cho G Kong J D Lee and K Yoon ldquop53mutations and human papillomavirus DNA in oral squamouscell carcinoma correlation with apoptosisrdquo British Journal ofCancer vol 78 no 3 pp 354ndash359 1998
[105] L LoMuzio G Pannone S Staibano et al ldquoSurvivin expressionin oral squamous cell carcinomardquo British Journal of Cancer vol89 no 12 pp 2244ndash2248 2003
[106] Y Jinbu K Tsukinoki N Miyagi et al ldquoExpression of survivinin oral squamous cell carcinomardquo Oral Med Pathol vol 11 pp41ndash44 2006
[107] C Jane A V Nerurkar N V Shirsat R B DeshpandeA D Amrapurkar and F R Karjodkar ldquoIncreased survivinexpression in high-grade oral squamous cell carcinoma a studyin Indian tobacco chewersrdquo Journal of Oral Pathology andMedicine vol 35 no 10 pp 595ndash601 2006
[108] Y-H Kim S-M Kim Y-K Kim S-P Hong M-J Kim andH Myoung ldquoEvaluation of survivin as a prognostic marker inoral squamous cell carcinomardquo Journal of Oral Pathology andMedicine vol 39 no 5 pp 368ndash375 2010
[109] N G Nikitakis J J Sauk and S I Papanicolaou ldquoThe role ofapoptosis in oral disease mechanisms aberrations in neoplas-tic autoimmune infectious hematologic and developmentaldiseases and therapeutic opportunitiesrdquo Oral Surgery OralMedicine Oral Pathology Oral Radiology and Endodontics vol97 no 4 pp 476ndash490 2004
[110] L L Loro O K Vintermyr A C Johannessen P G Liavaagand R Jonsson ldquoSuppression of Fas receptor and negative
Journal of Oral Diseases 11
correlation of Fas ligand with differentiation and apoptosis inoral squamous cell carcinomardquo Journal of Oral Pathology andMedicine vol 28 no 2 pp 82ndash87 1999
[111] N H Al-Rawi H Omer and S Al Kawas ldquoImmunohistochem-ical analysis of P53 and bcl-2 in benign and malignant salivaryglands tumorsrdquo Journal of Oral Pathology and Medicine vol 39no 1 pp 48ndash55 2010
[112] ANordkvist E Roijer G Bang et al ldquoExpression andmutationpatterns of p53 in benign andmalignant salivary gland tumorsrdquoInternational Journal of Oncology vol 16 no 3 pp 477ndash4832000
[113] V J Karja K J Syrjanen A-K Kurvinen and S M SyrjanenldquoExpression and mutations of p53 in salivary gland tumoursrdquoJournal of Oral Pathology and Medicine vol 26 no 5 pp 217ndash223 1997
[114] M Yanezez I Roa M Garcıa G Ibacache and M VillasecaldquoGene Bcl-2 protein expression in salivary gland tumorsrdquoRevista Medica de Chile vol 127 no 2 pp 139ndash142 1999
[115] L Jia R L Esguerra X Tang et al ldquoPrognostic value ofapoptosis and apoptosis-associated proteins in salivary glandadenoid cystic carcinomardquo Pathology International vol 54 no4 pp 217ndash223 2004
[116] Y Soini U Tormanen and P Paakko ldquoApoptosis is inverselyrelated to bcl-2 but not to bax expression in salivary glandtumoursrdquo Histopathology vol 32 no 1 pp 28ndash34 1998
[117] R M Nagler H Kerner S Ben-Eliezer I Minkov and O Ben-Itzhak ldquoPrognostic role of apoptotic Bcl-2 c-erbB-2 and p53tumor markers in salivary gland malignanciesrdquo Oncology vol64 no 4 pp 389ndash398 2003
correlation of Fas ligand with differentiation and apoptosis inoral squamous cell carcinomardquo Journal of Oral Pathology andMedicine vol 28 no 2 pp 82ndash87 1999
[111] N H Al-Rawi H Omer and S Al Kawas ldquoImmunohistochem-ical analysis of P53 and bcl-2 in benign and malignant salivaryglands tumorsrdquo Journal of Oral Pathology and Medicine vol 39no 1 pp 48ndash55 2010
[112] ANordkvist E Roijer G Bang et al ldquoExpression andmutationpatterns of p53 in benign andmalignant salivary gland tumorsrdquoInternational Journal of Oncology vol 16 no 3 pp 477ndash4832000
[113] V J Karja K J Syrjanen A-K Kurvinen and S M SyrjanenldquoExpression and mutations of p53 in salivary gland tumoursrdquoJournal of Oral Pathology and Medicine vol 26 no 5 pp 217ndash223 1997
[114] M Yanezez I Roa M Garcıa G Ibacache and M VillasecaldquoGene Bcl-2 protein expression in salivary gland tumorsrdquoRevista Medica de Chile vol 127 no 2 pp 139ndash142 1999
[115] L Jia R L Esguerra X Tang et al ldquoPrognostic value ofapoptosis and apoptosis-associated proteins in salivary glandadenoid cystic carcinomardquo Pathology International vol 54 no4 pp 217ndash223 2004
[116] Y Soini U Tormanen and P Paakko ldquoApoptosis is inverselyrelated to bcl-2 but not to bax expression in salivary glandtumoursrdquo Histopathology vol 32 no 1 pp 28ndash34 1998
[117] R M Nagler H Kerner S Ben-Eliezer I Minkov and O Ben-Itzhak ldquoPrognostic role of apoptotic Bcl-2 c-erbB-2 and p53tumor markers in salivary gland malignanciesrdquo Oncology vol64 no 4 pp 389ndash398 2003
