Carcinogenesis Advance Access published online on April 29, 2007
Carcinogenesis, doi:10.1093/carcin/bgm105
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A functional role of Cdx2 in ß-catenin signaling during trans-differentiation in endometrial carcinomas
1 Department of pathology
3 Division of Cell Tissue Culture, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, Kanagawa 228-8555, Japan
2 Department of carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo, Japan
4 Department of Pathology, Kurashiki Central Hospital, 1-1-1 Miwa, Kurashiki, 710-8602, Japan
Correspondence to Makoto Saegusa, M.D. TEL:+81-42-778-8996; FAX:+81-42-778-8441;e-mail: msaegusa{at}med.kitasato-u.ac.jp
Nuclear ß-catenin is required for charges 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 ß-catenin signaling during trans-differentiation of Em Ca cells. In clinical cases, Cdx2 immunoreactivity, along with increased mRNA signals, was found to overlap with nuclear accumulation of ß-catenin and p21Waf1 in morules, demonstrating an inverse correlation with cell proliferation. In cell lines, overexpression of active form ß-catenin resulted in a significant increase in endogenous Cdx2 expression at both mRNA and protein levels. Furthermore, the Cdx2 promoter was activated by TCF4-independent activated ß-catenin, as well as Cdx2 itself, through the region from-39 to +9 bp relative ti transcription start site. Cells overexpressinig 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 ß-catanin/TCF4-mediated transcriptional activation of target genes, including p14ARF and cyclin D1, probably through indirect mechanisms. These data suggest that overexpression of Cdx2 mediated by nuclearß-catenin and Cdx2 itself can cause an inhibition of Em Ca cell proliferation through upregulation of p21Waf1 expression, modulating ß-catenin/TCF4-mediated transcription. We therefore conclude that an association between Cdx2 and ß-catenin signaling may participate in induction of trans-differentiation of Em Ca cells.
Received January 23, 2007; revised March 31, 2007; accepted April 24, 2007.