Cdx1, a dispensable homeobox gene for gut development with limited effect in intestinal cancer

Abstract

The homeobox gene Cdx1 is involved in anteroposterior patterning in embryos and its expression selectively persists in the intestinal epithelium throughout life. In human colon cancers, Cdx1 is overexpressed in few cases and lost in the majority of adenocarcinomas. We used mouse models of gain and loss-of-function to investigate the role of Cdx1 in intestinal development and cancers. Transgenic mice overexpressing Cdx1 and knockout mice exhibited a morphologically normal intestine. Cell proliferation, specification into the four differentiated lineages and migration along the crypt-villus axis were unchanged compared to wild-type mice. Changing Cdx1 caused an inverse and dose-dependent modification of the expression of the paralogous gene Cdx2, indicating that Cdx1 fine-tunes Cdx2 activity. Transgenenic and knockout mice failed to spontaneously develop tumours. Overexpressing Cdx1 was without incidence on the frequency of intestinal tumours induced chemically by azoxymethane treatment or genetically in Apc D14/ þ mice. However, it augmented the severity of the tumours in Apc D14/ þ mice. Inversely, the loss-of-function of Cdx1 in knockout mice was without incidence on the growth of tumours induced by azoxymethane. We conclude that Cdx1 is dispensable for intestinal development and that its overexpression could increase malignancy in early stages of tumourigenesis.

CDX1 confers intestinal phenotype on gastric epithelial cells via induction of stemness-associated reprogramming factors SALL4 and KLF5

“…Cdx1 and Cdx2 were originally described as an oncoprotein and tumor suppressor, respectively, in intestinal cells (30,31). However, recent studies suggested that overexpression of Cdx1 has very limited contribution, if any, to the development of intestinal tumors (32,33). Hence, CDX1 could promote oncogenesis only when it is ectopic expressed in nonintestinal epithelial cells.…”

Gastrointestinal differentiation marker Cytokeratin 20 is regulated by homeobox gene CDX1

“…Our data suggest that CDX1 is the proximal determinant of intestinal differentiation, but it is probable that its activity depends on cooperation with CDX2. Recent work by Bonhomme et al (42) indicates that intestinal differentiation in a mouse knock out for CDX1 proceeds more or less normally. This suggests that CDX2 may substitute for CDX1 in its absence, but not vice versa, as CDX2 knock outs are lethal.…”

Genome-wide Analysis of CDX2 Binding in Intestinal Epithelial Cells (Caco-2)

“…45). The role of CDX1 has been controversial with regard to tumor development, but recent results indicate that CDX1 is dispensable for normal gut development and with only a limited effect on intestinal cancer (46). The expression of CDX1 has previously been shown to be affected by CDX2, and a putative CDX2 binding site was identified in the 5Ј end (30).…”