p16INK4a Is a β-Catenin Target Gene and Indicates Low Survival in Human Colorectal Tumors

Abstract

Background & Aims: Human colorectal carcinomas display an infiltrative front of invasion where tumor cells undergo an epithelomesenchymal transition associated with low survival. Epithelomesenchymal transition is regulated by a nuclear β-catenin accumulation, and subsequently, activation of β-catenin/TCF4 target genes similar to CYCLIN D1. Unexpectedly, these tumor cells are characterized by low proliferation, which correlates with the expression of the cell cycle inhibitor p16INK4A. Therefore, we investigated the molecular mechanism of the transcriptional regulation of p16INK4A in colorectal cancer and its correlation with survival. Methods: Molecular biological techniques were used for investigating the transcriptional mechanisms of the p16INK4A gene regulation. Moreover, p16INK4A expression was correlated with the 10-year survival of patients with colorectal carcinomas. Results: In colorectal carcinomas, expression of the p16INK4A gene is regulated by β-catenin/TCF4 and correlates with low survival rates of patients with tumors displaying an infiltrative front of invasion. Conclusions: β-catenin/TCF4 regulates cell cycle promoting (c-MYC, CYCLIN D1) and inhibiting genes (p16INK4A) at the same time in the mesenchymally differentiated tumor cells at the front of invasion. The function of p16INK4A seems to supersede in this context thus leading to low proliferation. Moreover, these tumor cells seem to govern the outcome of colorectal cancer independently of their proliferation. © 2009 AGA Institute.