Downregulation of the colon tumour-suppressor homeobox gene Cdx-2 by oncogenic ras

Abstract

Constitutive activation of the ras proto-oncogene is a frequent and early event in colon cancers, but the downstream nuclear targets are not fully understood. The Cdx-1 and Cdx-2 homeobox genes play crucial roles in intestinal cell proliferation and di erentiation. In addition, Cdx-2 is a colonic tumour-suppressor gene, whereas Cdx-1 has oncogenic potential. Here, we show that constitutive activation of ras alters Cdx-1 and Cdx-2 expression in human colonic Caco-2 and HT-29 cells that harbour a normal ras proto-oncogene. Oncogenic ras downregulates Cdx-2 through activation of the PKC pathway and a decline in activity of the Cdx-2 promoter AP-1 site. This decline results from a PKC-dependent decrease in the relative expression of c-Jun, an activator of Cdx-2 transcription, compared to c-Fos, an inhibitor of Cdx-2. Unlike Cdx-2, Cdx-1 is upregulated by oncogenic ras and this e ect is mediated by activation of the MEK1 pathway. These results indicate that oncogenic ras activation has opposite e ects on Cdx-1 and Cdx-2 expression through distinct signalling pathways and they provide the ®rst evidence for a functional link between ras activation and the downregulation of the Cdx-2 tumour-suppressor gene in colon cancer cells.

The intestine-specific homeobox gene Cdx2 decreases mobility and antagonizes dissemination of colon cancer cells

“…All these repressors downregulated Cdx2 and Snail was the most effective with a 40% reduction in Cdx2 mRNA (Figure 3c). Then, we tested the effects of these repressors on the Cdx2 promoter by cotransfection with the luciferase reporter plasmid pCdx2-1Luc (Lorentz et al, 1999). Corroborating the RT-qPCR results, overexpression of Zeb1, Snail or Slug reduced the activity of the promoter, with Snail showing the highest effect ( Figure 3d).…”

Vasopressin-mediated mitogenic signaling in intestinal epithelial cells

“…PKC⑀ has been shown to act as an oncogene when overexpressed in intestinal epithelial cells (53). PKC has also been implicated in the downregulation of the tumor suppressor gene Cdx-2 by oncogenic Ras in vivo (45). In actively cycling IEC-18 cells (cells growing in 5% serum), treatment with biologically active phorbol esters transiently inhibited cell cycle progression, which was noted 2-6 h after treatment (22,23).…”

Aberrant expression of CDX2 is closely related to the intestinal metaplasia and MUC2 expression in intraductal papillary neoplasm of the liver in hepatolithiasis

“…Forced expression of CDX2 in various intestinal epithelial cell lines inhibits cell proliferation and stimulates cell differentiation and apoptosis. 26,33 CDX2 restoration in CDX2-negative cells decreased the proliferative activity. 34 CDX2 expression decreases with the tumor grade in human colon cancers and in chemically induced tumors in the rat.…”

“…[22][23][24][25][26] Chronic acid exposure 25 and butyrate 23 induce the expression of CDX2, and phosphatase and tensin homolog deleted from chromosome 10 (PTEN) stimulate CDX2 protein expression, 22 reportedly. Inversely, a low concentration of TNF-a, 22 and oncogenic ras activation, 26 decrease CDX2 expression.…”