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Regulation of the tumor suppressor homeogene Cdx2 by HNF4α in intestinal cancer

Oncogene volume 32, pages 3782–3788 (2013)Cite this article

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Abstract

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 HNF4α and GATA6, are involved in Cdx2 regulation in the normal gut. Here we have studied the role of HNF4α in the mechanism of deregulation of Cdx2 in colon cancers. Crossing ApcΔ14/+ 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 HNF4α, unlike GATA6, exhibited a similar decrease to Cdx2 in genetic (Apcmin/+ and ApcΔ14/+) and chemically induced (Azoxymethane (AOM) treatment) models of intestinal tumors in mice. HNF4α and Cdx2 also exhibited a comparable deregulated pattern in human CRC. Correlated patterns were observed between HNF4α 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 HNF4α in human colon cancer cells using siRNA and in the colon of mice conditionally knocked out for the Hnf4α gene in the adult intestine (Hnf4αf/f;VilCreERT2 mice). Finally, the conditionally knocked out mice Hnf4αf/f;VilCreERT2 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 HNF4α is an important determinant of the reduced expression of the Cdx2 tumor suppressor gene in intestinal cancers. Consistently, similar to Cdx2, HNF4α exerts a tumor suppressor function in the colon in that its loss of function facilitates tumor progression.

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Acknowledgements

This work was supported by Inserm, Ligue contre le Cancer du Haut-Rhin and the Cancéropôle Grand-Est (France). TS was funded by the Association for International Cancer Research (AICR, UK) and by the Département de Mayotte (France), and Fl B by the Cancéropôle Ile-de-France.

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Author notes

  1. J-N Freund and I Duluc: These authors contributed equally to this work.

Authors and Affiliations

  1. Inserm, Unité 682, Strasbourg, France

    T Saandi, L Derbal-Wolfrom, F Benahmed, E Martin, B Duclos, J-N Freund & I Duluc

  2. Faculté de Médecine, Université de Strasbourg, Strasbourg, France

    T Saandi, L Derbal-Wolfrom, E Martin, B Duclos, J-N Freund & I Duluc

  3. Inserm, UMRS 872, Centre de Recherche des Cordeliers, Paris, France

    F Baraille, A-L Cattin, P Cardot & A Ribeiro

  4. UMRS 872, Université Pierre et Marie Curie, Paris, France

    F Baraille, A-L Cattin, P Cardot & A Ribeiro

  5. UMRS 872, Université Paris Descartes, Paris, France

    F Baraille, A-L Cattin, P Cardot & A Ribeiro

  6. Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, NY, USA

    F Benahmed

  7. Centre Hospitalier Universitaire, Service de Gastroentérologie, Strasbourg, France

    B Duclos

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Correspondence to I Duluc.

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Saandi, T., Baraille, F., Derbal-Wolfrom, L. et al. Regulation of the tumor suppressor homeogene Cdx2 by HNF4α in intestinal cancer. Oncogene 32, 3782–3788 (2013). https://doi.org/10.1038/onc.2012.401

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  • DOI: https://doi.org/10.1038/onc.2012.401

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