Tumor progression in CRC involves accumulation of genetic and epigenetic changes that ultimately lead to malignancy. E-cadherin downregulation occurs frequently and is widely believed to be a pivotal event in the transition to metastasis. Interestingly, studies of human GI tumors report p120 loss in some cases and dramatically upregulated p120 in others. In cultured cells, p120 overexpression induces significant changes in morphology and increases in cell motility, apparently through modulation of rho GTPases. We believe that the same mechanism drives the metastatic phenotype in E-cadherin deficient carcinomas, where p120 is stranded at high levels in the cytoplasm. Conversely, loss of p120 function in E-cadherin positive cells appears to disrupt E-cadherin function by a different mechanism. Our preliminary observations suggest that the colon carcinoma cell line SW48 contains mutations in both alleles of the p120 gene and restoring wild type p120 expression induces a striking correction of the epithelial phenotype. Thus, under normal circumstances, p 120 function is probably necessary for E-cadherin?s tumor suppressor role. Furthermore, in COLO205 cells, E-cadherin malfunction is induced by aberrant signaling through a p120-dependent pathway 13, suggesting that cadherin function can also be disrupted by post-translational regulation of p120. These observations suggest roles for p120 in the genesis and/or progression of CRC. Through the specific aims summarized below, this project seeks to understand the significance of defects in p120 expression and signaling in human colon oncogenesis and to test in a mouse model the efficacy of inhibiting metastasis by blocking p120 function in cell that have lost E-cadherin expression.
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