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

The Cdx1 homeobox gene encodes for an intestine-specific transcription fact or involved in the control of proliferation and differentiation of epitheli al cells. Although it has been indicated that Cdx1 may act as a proto-oncog ene in cultured fibroblasts, its direct role in the regulation of intestina l tumorigenesis has not been demonstrated. Here we show that expression of Cdx1 in an intestinal epithelial cell line (IEC-6) induces anchorage-indepe ndent growth in soft agar and promotes the formation of adenocarcinoma in v ivo, The phenotype of Cdx1-induced tumors was exacerbated when IEC-6/ Cdx1 cells were injected together with matrigel containing mitogens and extracel lular matrix components. These changes were correlated with an increase in the GTP-bound form of Ras, modulation of Cdc42 and Rho-A activities, and ac cumulation of phosphatidyl inositol 3 (PI3) kinase products. Moreover, comb ined 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 collaborat ion with Ras, Rho and PI3 kinase pathways, in transformation and tumorigene sis of intestinal epithelial cells.