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Homeobox gene Cdx1 regulates Ras, Rho and PI3 kinase pathways leading to transformation and tumorigenesis of intestinal epithelial cells

Oncogene volume 20, pages 4180–4187 (2001)Cite this article

Abstract

The Cdx1 homeobox gene encodes for an intestine-specific transcription factor involved in the control of proliferation and differentiation of epithelial cells. Although it has been indicated that Cdx1 may act as a proto-oncogene in cultured fibroblasts, its direct role in the regulation of intestinal tumorigenesis has not been demonstrated. Here we show that expression of Cdx1 in an intestinal epithelial cell line (IEC-6) induces anchorage-independent growth in soft agar and promotes the formation of adenocarcinoma in vivo. The phenotype of Cdx1-induced tumors was exacerbated when IEC-6/Cdx1 cells were injected together with matrigel containing mitogens and extracellular matrix components. These changes were correlated with an increase in the GTP-bound form of Ras, modulation of Cdc42 and Rho-A activities, and accumulation of phosphatidyl inositol 3 (PI3) kinase products. Moreover, combined inhibition of Ras/Rho and PI3 kinase signaling by syntethic inhibitors blocked colony formation of IEC-6/Cdx1 cells in soft agar. Taken together, these results demonstrate a direct involvement of Cdx1, and its collaboration with Ras, Rho and PI3 kinase pathways, in transformation and tumorigenesis of intestinal epithelial cells.

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Acknowledgements

We thank A Östman, T Sjöblom, K Pietras, P Aspenström and S Edlund for help, advice and reagents along the course of this project. We acknowledge C-H Heldin and A Blaukat for critical comments on the manuscript. This work was supported by grants from the Swedish Cancer Foundation (I Dikic), the Ligue Nationale Contre le Cancer Comité des Bouches du Rhône (J Iovanna), the Association pour la Recherche sur le Cancer (J Iovanna) and an EMBO short-term fellowship to P Soubeyran. P Soubeyran is a fellow of the ARC and I Dikic is a fellow of the Boehringer Ingelheim Fonds.

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  1. Bernd-Uwe Barth

    Present address: Section for Natural Sciences, Södertörns högskola, Box 4101, SE-141 04, Huddinge, Sweden

Authors and Affiliations

  1. Ludwig Institute for Cancer Research, Box 595, Husargatan 3, Uppsala, S-75124, Sweden

    Kaisa Haglund, Bernd-Uwe Barth & Ivan Dikic

  2. U.315 INSERM, Laboratoire de Physiologie et Pathologie Digestives, 46 Boulevard de la Gaye, Marseille, 13009, F, France

    Philippe Soubeyran & Juan Iovanna

  3. Hôpital Nord, Chemin des Bourrellys–13915 Marseille, France

    Stéphane Garcia

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  1. Philippe Soubeyran
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Correspondence to Ivan Dikic.

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Soubeyran, P., Haglund, K., Garcia, S. et al. Homeobox gene Cdx1 regulates Ras, Rho and PI3 kinase pathways leading to transformation and tumorigenesis of intestinal epithelial cells. Oncogene 20, 4180–4187 (2001). https://doi.org/10.1038/sj.onc.1204551

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