A functional role of Cdx2 in β-catenin signaling during transdifferentiation in endometrial carcinomas

Abstract

Nuclear β-catenin is required for changes in morphology from glandular to morular phenotypes of endometrial carcinoma (Em Ca) cells, with activation of p14ARF/p53/p21Waf1 and alteration of p16INK4A/pRb pathways. Having demonstrated previously that the homeodomain transcription factor Cdx2 increases markedly during intestinal epithelial cell differentiation, we have examined its effects in β-catenin signaling during transdifferentiation of Em Ca cells. In clinical cases, Cdx2 immunoreactivity, along with increased mRNA signals, was found to overlap with nuclear accumulation of β-catenin and p21Waf1 in morules, demonstrating an inverse correlation with cell proliferation. In cell lines, over-expression of active form β-catenin resulted in a significant increase in endogenous Cdx2 expression at both mRNA and protein levels. Furthermore, the Cdx2 promoter was activated by T-cell factor 4 (TCF4) -independent activated β-catenin, as well as Cdx2 itself, through the region from -39 to +9 bp relative to transcription start site. Cells over-expressing exogenous Cdx2 showed high levels of p21Waf1 expression due to stabilization of the mRNA status, resulting in significant decrease in the proliferation rate, in contrast to the lack of apparent changes in morphology. Moreover, transfected Cdx2 could inhibit β-catenin/ TCF4-mediated transcriptional activation of target genes, including p14ARF and cyclin D1, probably through indirect mechanisms. These data suggest that over-expression of Cdx2 mediated by nuclear β-catenin and Cdx2 itself can cause an inhibition of Em Ca cell proliferation through up-regulation of p21Waf1 expression, modulating β-catenin/TCF4-mediated transcription. We therefore conclude that an association between Cdx2 and β-catenin signaling may participate in induction of transdifferentiation of Em Ca cells. © The Author 2007. Published by Oxford University Press. All rights reserved.