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Research progression21/07/2009
By
Tanan Bejrananda, MD.
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Wnt signaling and CA
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Wnt signaling in CA colon
Outline
Background
Research question
Study design
Material and method
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Background
Identified through genetic studies indrosophila.
Highly conserved in evolution and are very
important in animal development
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Wnts
Wnt proteins released from or presented on thesurface of signaling cells act on target cells bybinding to Frizzled (Fz)/LDL-related protein(LDR) complex at the cell surface.
Receptors Frizzled receptors, like GPCRs, are transmembrane
proteins that span 7 timesthe plasma membrane.
Their ligand-binding site is exposed outside the
surface of the cell. Their effector site extends into the cytosol.
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Wnt
Wnt proteins form a family of highlyconserved secreted signaling moleculesthat regulate cell-to-cell interactions during
embryogenesis. Insights into the mechanisms of Wnt action
have emerged from several systems:
genetics in Drosophila and Caenorhabditiselegans; biochemistry in cell culture andectopic gene expression inXenopus
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Wnt
Mutations in Wnt genes or Wnt pathwaycomponents lead to specificdevelopmental defects, while various
human diseases, including cancer, arecaused by abnormal Wnt signaling.
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As currently understood, Wnt proteins
bind to receptors of the Frizzled and LRPfamilies on the cell surface.
Through several cytoplasmic relaycomponents, the signal is transduced tobeta-catenin, which enters the nucleus
and forms a complex with TCF to activatetranscription of Wnt target genes
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Wnt pathway
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Ligands Their ligands are Wnt
proteins. These get
their name from two ofthe first to bediscovered, proteinsencoded by
wingless (wg) in
Drosophila and itshomolog
Int-1 in mice.
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Fz receptors transducesignals to intra-cellularproteins including Dsh,GSK-3, Axin, APC and
-catenin
Nuclear -catenininteracts with lymphoidenhancer-binding factor
1/T cell-specifictranscription factor(LEF/TCF) to affecttranscription.
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In vertebrates, Wntproteins are inhibited bydirect binding to eithersecreted frizzled-relatedprotein (SFRP) or Wntinhibitory factor (WIF).
SFRP is similar insequence to the cysteine-rich domain (CRD) of
Frizzled, one of the Wntreceptors.
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GSK-3b dependentphosphorylation,ubiquitination and
complex formation withthe proteins axin andAPC are important toregulate the cytoplasmicstability of beta-catenin
protein in the wnt-signaltransduction pathway
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Interaction with TCFtranscription factorsand the transactivation
domains of beta-catenin areinstrumental toactivate/derepress wnt-target genes in thenucleus.
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Complex formation with cadherins and alpha-catenin atthe plasma membrane is essential for the role of beta-catenin in cell adhesion.
In vertebrate development, loss of a single Wnt gene can
produce dramatic phenotypes that range from embryoniclethality and CNS abnormalities to kidney and limbdefects
These diverse phenotypes indicate that the Wnt pathway
has distinct transcriptional outputs.
In many cases, the cell, rather than the signal,determines the nature of the response, and up- or down-regulation of Wnt target genes is cell-type specific.
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WNT TARGET GENES ANDFEEDBACK LOOPS
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WNT SIGNALING IN CANCER
AND HUMAN DISEASE In adults, mis-regulation of the Wnt
pathway also leads to a variety of
abnormalities and degenerative diseases
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Current evidence indicates thatthe Wnt cascade is the singlemost dominant force incontrolling cell fate along thecrypt-villus axis.
In Tcf4 -/- neonatal mice, thevillus epithelial compartmentappears unaffected but thecrypt progenitor compartmentis entirely absent, implying that
physiological Wnt signalling isrequired for maintenance ofthe crypt progenitorphenotype.
From crypt physiology to colon cancer
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The Wnt pathway in colon cancer
The APC gene was originally discovered to bethe culprit in a hereditary cancer syndrometermed familial adenomatous polyposis (FAP).
FAP patients, inheriting one defective APCallele, develop large numbers of colon polyps, oradenomas, early in life.
Individual polyps are clonal outgrowths of
epithelial cells in which the second APC allele isinactivated.
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Mutational inactivation of APC leads to theinappropriate stabilization of b-catenin, implyingthat the absence of functional APC transforms
epithelial cells through activation of the Wntcascade.
In some cases of colorectal cancer in which APCis not mutated, the scaffolding protein axin 2 is
mutant, or activating (oncogenic) point mutationsin b-catenin remove its N-terminal Ser/Thrdestruction motif.
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Multiple studies have used a candidategene approach to address the nature ofthe Tcf4 target gene programme in
colorectal cancer.
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Title :
What are the relating of Wntsignalingwith Colorectal cancer in Thailand ?
Study Design :
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Primary outcome
Secondary outcome
Study Design : Material and
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Design
Study Design : Material and
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Patient
- All patients with CA colon were admitted
between to in SongkhlanagarindHospital in Hadyai, Thailand.
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Exclusion criteria
Study Design : Material and
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Data collection
Study Design : Material and
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Statical study
Study Design : Material and
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