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Understanding the Molecular Mechanisms of Wnt/B -Catenin Signalling in Cancer

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Title Understanding the Molecular Mechanisms of Wnt/B -Catenin Signalling in Cancer
 
Creator Naidu , G Kiran Kumar
 
Subject Cancer Biology and Inflammatory Disorder Division
 
Description In spite of significant advancements in diagnosis and treatment, cancer is still a big threat to society. This is the second most common disease for maximum deaths in the world and it accounts for about 7% deaths in India. Prostate cancer is the most common cancer in males in
western countries and breast cancer is the most prevalent cancer in women in India. It has long been appreciated that multiple signaling pathways coexist within the cell during cancer development. Many examples have been presented in which these pathways can influence each other’s behaviour through crosstalk. The puzzle that remains for researchers is to determine the extent and relevance of such crosstalk during cancer development as well as progression.
Wnt/�-catenin and EGFR pathways are important in cancer development and often aberrantly activated in human cancers. However, it is very important to understand the
mechanism responsible for their activation and the relation between them. This study reveals an interesting mechanism of EGFR expression by transcriptionally active �-catenin in GSK3� inactivated prostate cancer cells that eventually leads to its enhanced proliferation and survival.
Expressions of �-catenin and EGFR are elevated in various cancers specifically in prostate cancer (PCa) cells, DU145. When GSK3� is inactivated in these cells, �-catenin gets stabilized, phosphorylated at Ser552 by PKA, accumulates in the nucleus and regulates the expression of its target genes that include EGFR. Chromatin Immunoprecipitation (ChIP) and promoter analysis revealed that the EGFR promoter gets occupied by transcriptionally active �-catenin
when elevated in GSK3� inactivated cells. This phenomenon not only leads to increased expression of EGFR but also initiates the activation of its downstream molecules such as
ERK1/2 and Stat3. P68 is overexpressed in cancers which has been implicated in a variety of processes, including rearrangement of RNA secondary structures, RNA splicing, gene transcription and tumor development. We found that �-catenin directly induce transcription of the p68 promoter
or indirectly through oncogenic protein c-Myc in human as well as mouse cancer cells. The p68 promoter contains putative consensus sequences of TCF4 and c-Myc. TCF4 putative site isn critical for activation by �-catenin as analyzed by promoter analysis using luciferase assay.
Moreover we have found that �-catenin and TCF4 occupies the p68 promoter. Here we have also analyzed positive feedback regulation of TCF4 expression by p68. These consequences of
�-catenin/TCF4 mediated p68 expression plays a crucial role in enhanced migratory and invasive potential of triple negative breast cancer cells MDA-MB-231 and mouse aggressive
4T1cells. These findings strongly indicate that Wnt signaling plays an important role in cancer progression by upregulating p68 and EGFR expression which consequently leads to tumor progression.
 
Date 2013
 
Type Thesis
NonPeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/1984/1/Thesis_GKKN%2DUnderstanding_the_molecular_Mechanisms_of_Wnt_betacatenin_signaling_in_cancer.pdf
Naidu , G Kiran Kumar (2013) Understanding the Molecular Mechanisms of Wnt/B -Catenin Signalling in Cancer. PhD thesis, Calcutta University.
 
Relation http://www.eprints.iicb.res.in/1984/