Regulation of the tumor suppressor homeogene Cdx2 by HNF4alpha in intestinal cancer.
Fiche publication
Date publication
août 2013
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DULUC Isabelle, Dr FREUND Jean-Noël, Dr MARTIN Etienne
Tous les auteurs :
Saandi T, Baraille F, Derbal-Wolfrom L, Cattin AL, Benahmed F, Martin E, Cardot P, Duclos B, Ribeiro A, Freund JN, Duluc I
Lien Pubmed
Résumé
The gut-specific homeotic transcription factor Cdx2 is a crucial regulator of intestinal development and homeostasis, which is downregulated in colorectal cancers (CRC) and exhibits a tumor suppressor function in the colon. We have previously established that several endodermal transcription factors, including HNF4alpha and GATA6, are involved in Cdx2 regulation in the normal gut. Here we have studied the role of HNF4alpha in the mechanism of deregulation of Cdx2 in colon cancers. Crossing Apc(Delta14/+) mice prone to spontaneous intestinal tumor development with pCdx2-9LacZ transgenic mice containing the LacZ reporter under the control of the 9.3-kb Cdx2 promoter showed that this promoter segment contains sequences recapitulating the decrease of Cdx2 expression in intestinal cancers. Immunohistochemistry revealed that HNF4alpha, unlike GATA6, exhibited a similar decrease to Cdx2 in genetic (Apc(min/+) and Apc(Delta14/+)) and chemically induced (Azoxymethane (AOM) treatment) models of intestinal tumors in mice. HNF4alpha and Cdx2 also exhibited a comparable deregulated pattern in human CRC. Correlated patterns were observed between HNF4alpha and Cdx2 in several experimental models of human colon cancer cell lines: xenografts in nude mice, wound healing and glucose starvation. Furthermore, Cdx2 decreased by knocking down HNF4alpha in human colon cancer cells using siRNA and in the colon of mice conditionally knocked out for the Hnf4alpha gene in the adult intestine (Hnf4alpha(f/f);VilCre(ERT2) mice). Finally, the conditionally knocked out mice Hnf4alpha(f/f);VilCre(ERT2) treated with the carcinogen AOM developed colorectal tumors earlier than wild-type mice, as previously reported for mice with a reduced Cdx2 expression. In conclusion, this study provides evidence that the downregulation of HNF4alpha is an important determinant of the reduced expression of the Cdx2 tumor suppressor gene in intestinal cancers. Consistently, similar to Cdx2, HNF4alpha exerts a tumor suppressor function in the colon in that its loss of function facilitates tumor progression.
Référence
Oncogene. 2013 Aug 8;32(32):3782-8