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

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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 synthethic 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.