Cyclo-oxygenase-2 expression in oral squamous cell carcinoma

1Journal of Cancer Research and Therapeutics - ??? - Volume ?? - Issue ?

Maryam Seyedmajidi, Shahryar Shafaee1, Sepideh Siadati2, Monireh Khorasani3, Ali Bijani4, Nafiseh Ghasemi3

Department of Oral and Maxillofacial Pathology of Dental Materials Research Center, Dental Faculty, 1Department of Pathology of Cellular and Molecular Biology Research Center, 2Department of Pathology, Faculty of Medicine, 3Students Research Committee, 4Non‑communicable Pediatrics Diseases Research Center, Babol University of Medical Sciences, Babol, Iran

For correspondence: Dr. Maryam Seyedmajidi, Department of Oral and Maxillofacial Pathology, Dental Materials Research Center, Dental Faculty, Babol University of Medical Sciences, Babol, Iran. E‑mail: [email protected]

Cyclo‑oxygenase‑2 expression in oral squamous cell carcinoma

ABSTRACTBackground: Many evidences showed that cyclooxygenase‑2 (COX‑2), an enzyme that catalyzes the synthesis of prostaglandins, has an important role in carcinogenesis. It has been observed in experimental models that selective COX‑2 inhibitors suppress the formation of tumors including tongue carcinoma. The aim of this study was to investigate the immunohistochemical expression of COX‑2 in oral squamous cell carcinoma (OSCC) compared to normal oral mucosa and oral dysplasia.

Materials and Methods: A total of 60 paraffined blocks (20 cases of OSCC, 20 cases of oral epithelial dysplasia and 20 cases of normal oral mucosa were included in this study and immunohistochemical staining was done for COX‑2 expression. From each sample, 5 high power fields were assessed to determine the percentage of stained cells and staining intensity. Immunoreactivity was obtained by multiplying the above two cases. Data were analyzed with using the Kruskal‑Wallis test ANOVA, Mann‑Whitney test and least significant difference and P < 0.05 was declared as significant.

Results: High level of COX‑2 expression was found in OSCC and dysplasia compared to normal mucosa. Furthermore, a positive correlation was found between COX‑2 expression and severity of dysplasia. However, no significant difference between low grade and high grade tumors was found.

Conclusion: The result of the present study supports from the role of COX‑2 in carcinogenesis and progression of premalignant lesion to malignancy.

KEY WORDS: Cycloxygenase‑2, dysplasia, immunohistochemistry, normal oral mucosa, squamous cell carcinoma

INTRODUCTION

Oral cancer is a major health problem world‑wide. Every year more than 300,000 new cases of oral cancer are diagnosed and about 95% of them are squamous cell carcinomas (SCC).[1] Despite the progress that has been made in diagnostic techniques, the incidence of SCC is high in many parts of the world including Asia. Recent studies showed an increased incidence of primary oral squamous cell carcinoma (OSCC) in young patients in Iran.[2]

Despite recent advances in the areas of surgery, radiotherapy and chemotherapy, the survival rate of patients suffering from these tumors is low.[1] Therefore, new molecular targets for the prevention and treatment of head and neck SCC and related cancers seem to be necessary.

Cyclooxygenases (COXs) catalyze the synthesis of prostaglandins from arachidonic acid. There are two isoforms of COX. One is expressed constitutively (COX‑1) and the other is inducible (COX‑2).[3,4] The COX‑2 gene is an early‑response gene that is induced by growth factors, oncogenes, carcinogens, cancer‑causing

phorbol esters, several cytokines, hypoxia and ultraviolet radiation and it is expressed in many neoplastic processes, it stimulates cell division and angiogenesis and inhibits apoptosis.[3‑6] Constitutive isoform, COX‑1, is not necessarily affected by these factors and is expressed in many tissues during physiological processes.[4]

Many evidences from different experimental systems showed that COX‑2 has an important role in carcinogenesis. COX‑2 in up regulated in transformed cells[3,7] and in malignant tumors.[8‑11]

Previous studies have shown that COX‑2 expression in OSCC is higher than in normal epithelium. However, no significant difference exists in COX‑2 expression between high grade and low grade tumors.[2,12]

The studies that have been done on these enzyme inhibitors have shown successful results.[13,14] Non‑specific inhibitors of COX, the non‑steroidal anti‑inflammatory drugs and COX‑2 specific inhibitors, have a significant effect in reducing the initiation and progression of tumors in both animal models and in the treatment of cancer

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Seyedmajidi, et al.: COX‑2 expression in OSCC

2 Journal of Cancer Research and Therapeutics - ??? - Volume ?? - Issue ?

patients.[15] The aim of the present study was to investigate the immunohistochemical expression of COX‑2 in OSCC compared with oral dysplasia and normal oral mucosa.

MATERIALS AND METHODS

SamplingIn this study, 60 formalin‑fixed paraffin embedded samples including 20 cases of OSCC, 20 cases of oral dysplasia and 20 cases of normal oral mucosa were withdrawn from the archives of Oral and Maxillofacial Pathology department, Babol university of medical sciences (2004‑2013). The design of this study was approved by the Ethics in Research Committee of Babol University of Medical Sciences. Five‑micron sections were prepared from paraffined blocks and stained with hematoxylin and eosion. The microscopic slides were assessed by two independent pathologist observers without prior knowledge of the clinical data to classify the histologic grades of oral dysplasia and OSCC according to the World Health Organization Classification of Tumors.[16] In the cases of disagreement, the pathologists discussed the findings and performed the final evaluation. Included samples in this study were taken from the patients who had not received any treatment for their disease. Colon carcinoma was used as positive control. Negative control was established by omission of the primary antibody.

ImmunohistochemistryImmunohistochemical staining was performed according to Novolink Polymer Detection System (Product NO: RE7140‑K). 3 micron sections cut from paraffined blocks were deparaffinized in xylene and rehydrated in graded alcohol. For antigen retrieval, the deparaffinized slides in citrate buffer with pH = 6 for 15 min were put in the microwave oven. Endogenous peroxidase activity was blocked by incubating the sections with 3% H

2O

2. Non‑specific antibody binding was blocked by

pretreatment with protein block solution. Then the sections were incubated with the primary antibody (ab15191, Abcam) in a dilution of

1

500

These sections were washed with Tris‑Buffered Saline (pH = 7.4). In next step post primary block solution was used to enhance the penetration of the subsequent polymer reagent. The sections were then incubated with the secondary antibody for 30 min. Diaminobenzidine was used as chromogen. The sections were counterstained with Harris hematoxylin. Finally slides were dehydrated in graded alcohol and then cleaned with xylene and covered with a coverslip.

Evaluation of COX‑2 immunostainingPrepared slides were observed by two independent pathologists with an optical microscope and ×400 magnifications. Five high‑power fields were selected from each sample and at least 700 epithelial cells were evaluated. The percentage of stained

cells observed in the fields was scored as follows: 0 (0%), 1 (1% ≥), 2 (1‑10%), 3 (11‑33%), 4 (34‑66%) or 5 (67‑100%) respectively. Staining intensity was assessed on a scale from 0 to 3 (negative, weak, moderate and strong). As an internal positive control, smooth muscle cells were used in the samples and the immunoreactivity (total score) was determined by multiplying the percentage of positive cell score and staining intensity score.[17] In the cases of disagreement, the pathologists discussed the findings and performed the final evaluation.

Statistical analysisTo compare the three groups in terms of the immunoreactivity (total score) Kruskal‑Wallis test and ANOVA were used. Mann‑Whitney test was used to evaluate the association between COX‑2 expression and various degrees of dysplasia and SCC. For the comparison of COX‑2 expression between each two groups, Mann‑Whitney test and least significant difference were used.

FindingsA total of 60 samples including 20 cases of OSCC (5 male patients and 15 female patients with a mean age of 66.50 ± 14.24 years) and 20 cases of oral dysplasia (10 male patients and 10 female patients with a mean age of 58.15 ± 20.56 years) and 20 cases of normal oral mucosa (6 male patients and 14 female patients with a mean age of 35.20 ± 14.351) were included in this study. The location of each lesion is brought in Table 1.

The comparison of COX‑2 expression between the three studied groups and between OSCC and normal oral mucosa, epithelial dysplasia and normal mucosa showed a statistically significant difference (P < 0.001). Furthermore, a significant difference between OSCC and epithelial dysplasia was observed (P = 0.049). The results of immunoreactivity are reported in Table 2 [Figures 1 and 2].

Average total score of immunoreactivity in each group and the comparison between three groups are shown in Figure 3.

Among specimens of dysplasia in this study, 8 cases (40%) showed mild dysplasia, 6 cases (30%) moderate dysplasia, 6 cases (30%) severe dysplasia and among samples of SCC, 7 samples (35%) were Grade I, 8 cases (40%) were Grade II and 5 cases (25%) were Grade III respectively.

Table 1: Distribution of location of lesions in samples of SCC, epithelial dysplasia and normal oral mucosaLocation Sample type (number (%))

Normal oral mucosa

Epithelial dysplasia

SCC

Buccal mucosa 0 (0) 6 (30) 8 (40)Tongue 0 (0) 4 (20) 2 (10)Alveolar ridge 0 (0) 1 (5) 5 (25)Palate 0 (0) 1 (5) 3 (15)Gingiva 20 (100) 7 (35) 2 (10)Lip 0 (0) 1 (5) 0 (0)Total 20 (100) 20 (100) 20 (100)SCC=Squamous cell carcinomas





In various grades of epithelial dysplasia, statistically significant difference was observed in COX‑2 expression. However, there was no significant difference between different grades of SCC (according to the distribution points in the diagram) (P = 0.398) [Figure 4].

DISCUSSION

The results of the present study showed a higher expression of COX‑2 in OSCC compared with dysplasia and normal oral mucosa, which confirmed the role of COX‑2 in carcinogenesis.

The overexpression of COX‑2 has been reported in different types of human carcinomas, including head and neck and esophageal cancers.[18,19] Chemopreventive effects of selective COX‑2 inhibitors and their inhibitory effect on the growth and metastasis of tumors and enhancement of the anticancer effects of radiotherapy and chemotherapy in experimental animals[13] and human models,[20] is an indicating the role of this protein in carcinogenesis.

COX‑2 is an inducing enzyme that is inducible in various pathological conditions of tissues by growth factors, inflammatory stimuli, oncogenes and tumor promoters. COX‑2 promotes the inhibition and progression of cancers by various mechanisms acting at different stages of malignant disease.[21] COX‑2 contributes to carcinogenesis via a two prong effect: Direct effects on tumor cells by promoting mitotic activity and conversion of pro‑carcinogens to carcinogens and indirect effects on non‑tumoral cells by nurturing tumoral blood vessels and modulating of immune cells.[22] During tumorogenesis, COX‑2 induces angiogenic factors such as vascular endothelial growth factor (VEGF) and fibroblastic growth factor through the prostaglandin cascade and thus causes angiogenesis and tumor growth.[23] Gallo et al. in their study have reported the critical role of COX‑2 in angiogenesis of head and neck cancer by regulating the expression of VEGF.[24]

Prostaglandins particularly, E types, increase neoplastic cell proliferation, angiogenesis, invasion and metastasis. Prostaglandin E2 also inhibits tumor necrosis factor and

Figure 1: Cyclooxygenase-2 immunohistochemical staining in normal oral mucosa (×400)

Table 2: Results of immunohistochemical staining with cyclooxygenase‑2 marker in terms of the immunoreactivity (total score) in normal mucosa, dysplasia and oral SCCType of sample Total score (number (%))

0 1 2 3 4 5 6 8 9 10 12 15Normal oral mucosa 19 (95) 1 (5) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)Epithelial dysplasia 0 (0) 1 (5) 5 (25) 2 (10) 1 (5) 0 (0) 4 (20) 4 (20) 0 (0) 2 (10) 0 (0) 1 (5)SCC 0 (0) 0 (0) 1 (5) 2 (10) 3 (15) 1 (5) 1 (5) 5 (25) 1 (5) 4 (20) 0 (0) 2 (10)SCC=Squamous cell carcinomas

Figure 2: Cyclooxygenase-2 immunohistochemical staining in oral dysplasia and oral squamous cell carcinoma (SCC): (a) Mild dysplasia, (b) moderate dysplasia, (c) severe dysplasia, (d) well differentiated SCC, (e) moderately differentiated SCC and (f) poorly differentiated SCC

d

cb

f

a

e





induces interleukin‑10, a cytokine with immunosuppressive effects. It also appears that overexpression of COX‑2, changes cell adhesion and response to regulatory signals and it also inhibits apoptosis.[18,21,25] Immunohistochemical analysis shows overexpression of COX‑2 in multiple cancers including the skin,[26] breast,[27] lung,[11] head and neck[18] and colorectal.[28] In some of these malignancies, overexpression of COX‑2 is associated with poor prognosis and low survival rate.[25,28] In present study, overexpression of COX‑2 in OSCC compared with dysplasia and normal mucosa was observed.

Shibata et al. revealed that increased expression of COX‑2 in dysplastic epithelia and its overexpression in OSCC reflects the role of this enzyme in the early stages of oral carcinogenesis as well as in subsequent events that involved in tumor progression.[29] These results are similar to the results reported by Pandey et al. They studied COX‑2 expression in normal mucosa, oral dysplasia and OSCC. The results showed higher expression of COX‑2 in OSCC compared with premalignant lesions and normal oral mucosa.[30]

In a study by Zhang et al. showed that COX‑2 expression is higher in oral dysplasia and SCC than normal oral mucosa.[14] This finding is in consistent with the results of the present study. Similar findings have been reported by Chan et al.[18] for head and neck SCC and by Amirchaghmaghi et al.[2] and Nagatsuka et al.[31] about OSCC.

The above results is in contrary with the results of Shibata et al., they investigated the COX‑1 and COX‑2 expression in oral carcinogenesis and showed that COX‑2 expression is higher in oral dysplasia compared with OSCC.[29]

Pontes et al. compared the COX‑2 expression in OSCC and oral leukoplakia and inflammatory fibrous hyperplasia. The difference in COX‑2 expression was statistically significant only when the moderate dysplasia was compared with inflammatory fibrous hyperplasia.[32]

Shamma et al. introduced COX‑2 as a sensitive marker for high grade dysplasia of the esophagus and expressed that this enzyme is involved in the early stages of esophageal SCC.[19] Nathan et al. also found similar results about head and neck dysplasia.[17] This finding is not consistent with the results of the present study. The mechanisms of COX‑2 overexpression during oral carcinogenesis are still not well‑understood. It is thought that in breast,[33] ovarian[34] and gastric cancers,[35] COX‑2 overexpression is as a result of inactivation of the intrinsic mechanisms, such as inactivation of tumor suppressor genes, like p53 and activation of proto‑oncogene such as Ras, human epidermal growth factor receptor 2/neu[33,34] and the messenger ribonucleic acid stability factor HuR.[35]

In this study, a positive correlation was found between the expression of COX‑2 and severity of dysplasia. Nagatsuka et al.[31] and Shibata et al.[29] also found similar results. These results are also in agreement with the study of Shamma et al. In their study, the expression of COX‑2 progressively increased from normal esophagus to low grade dysplasia and the highest levels of COX‑2 expression were found in severe dysplasia. Then it is gradually decreased during progression from primary cancer to the advanced SCC. This study showed that COX‑2 may be involved in regulation of cell proliferation from normal esophagus to severe dysplasia.[19] Furthermore Nathan et al. reported COX‑2 overexpression in high grade dysplasia of head and neck and they mentioned that COX‑2 inhibitors may be effective in chemoprevention of head and neck cancer.[17]

The results reported in this study about the grades of malignancy, are agreed with studies that found no correlation between the expression of COX‑2 and the grade of malignancy. In the study performed by Pandey et al.[30] and Amirchaghmaghi et al.[2] no significant difference was observed in COX‑2 expression between different grades of OSCC, these findings confirmed the results of present study. Itoh et al. also found no association between COX‑2 expression and histological grades of tumor.[25]

Figure 3: Average total score in oral normal oral mucosa, oral epithelial dysplasia and oral squamous cell carcinoma and comparison between the three groups

Figure 4: Changes in total score based on the increasing severity of dysplasia and an increase in grade of squamous cell carcinoma





In agreement with our study, Goulart Filho et al. also found no significant difference in COX‑2 expression between low grade and high grade OSCC.[12]

On the other hand, our results is in conflict with the studies that showed an inverse correlation between COX‑2 expression and the histological grade of malignancy and also with the studies that revealed the COX‑2 expression is higher in poorly differentiated OSCC. As mentioned above, Shamma et al. in their study reported that COX‑2 expression gradually decrease during progression from early esophageal cancer to advanced SCC.[19]

Nagatsuka et al. showed a correlation between COX‑2 expression and tumor grade. In their study, poorly differentiated OSCC showed intense and diffuse staining and well and moderate differentiated OSCC showed local staining around nests of tumor.[31]

Shibata et al. found an inverse correlation between COX‑2 expression and histological differentiation of OSCC.[29]

Furthermore Cao et al. in their study have reported that expression of COX‑2 in OSCC is associated with histological grade.[36] Renkonen et al. reported that overexpression of COX‑2 in tongue SCC is almost associated with histological grade.[37]

The increased expression of COX‑2 during oral carcinogenesis may depend on the developmental stage of the tumor, as well as etiologic factors such as the types of mutations and distinct types of injuries affecting different regions. Thus there are a wide variation in pathways and factors that lead to or affect oral carcinogenesis.[12] In addition, further studies are required to determine which of these mechanisms are more important in the development and progression of OSCC.

CONCLUSION

The results of present study revealing the differences in immunohistochemical COX‑2 expression between dysplasia and normal oral mucosa showed its role in the carcinogenesis. The difference between the expression of this enzyme in OSCC and dysplasia supports its role in the next events while progression from premalignant lesions to malignancy. However, it does not seem that COX‑2 is effective in promoting carcinoma. Thus according to obtained results, COX‑2 may be used for molecular target therapy. It seems that the COX‑2 inhibitors could be used in preventing the transformation of premalignant lesions to malignancies in oral cavity or formation of mucosal premalignant lesions.

ACKNOWLEDGMENTS

The present study is the result of a research project No. 9133421, approved by the Research Council of Babol University of Medical Sciences and the thesis of a dentistry student ‑ Dr. Monireh Khorasani. The authors would like to thank the Deputy of Research and

Technology of Babol University of Medical Sciences for financially supporting the project and also Mr. Mohsen Aghajanpour in the Cellular and Molecular Biology Research Center and Mr. Obeid Mohammadi of this university for his sincere cooperation in performing the immunohistochemical staining.

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Source of Support: The authors would like to thank the Deputy of Research and Technology of Babol University of Medical Sciences for financially supporting the project and also Mr. Mohsen Aghajanpour in the Cellular and Molecular Biology Research Center and Mr. Obeid Mohammadi of this university for his sincere cooperation in performing the immunohistochemical staining, Conflict of Interest: None declared.



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Cyclo-oxygenase-2 expression in oral squamous cell carcinoma

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