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Wnt signaling is often constitutively active in colorectal cancer cells. The expression of the intestinal specific transcription factor CDX2 is found to be transiently decreased in invasive cells at the tumor/stroma interface. A recent ChIP-Seq study has indicated that several Wnt signaling-related genes are regulated by CDX2. The aim was to investigate the role of decreased CDX2 level on the expression ofAPC,AXIN2andGSK3βin migrating colon cancer cells at the invasive front. CDX2-bound promoter and enhancer regions fromAPC,AXIN2andGSK3βwere analyzed for gene regulatory activity and the expression pattern of APC and GSK3β at the invasive front was evaluated by immunohistochemical procedures. Transfection of intestinal and non-intestinal cell lines demonstrated that CDX2 activatedAPCandAXIN2promoter activities via intestinal cell-specific enhancer elements. SuppressedCDX2expression was associated with endogenous downregulation ofAPCandAXIN2expression in Caco-2 cells but did not affectGSK3βexpression. Furthermore, elevated levels of nuclear β-catenin and reduced levels of cytoplasmic APC were correlated to a low CDX2 expression in migrating colon cancer cellsin vivo. These results suggest that a low CDX2 level has influence on the Wnt signaling in invasive colon cancer cells possibly promoting cellular migration.

carcinogenesis

Regulation of               APC               and               AXIN2               expression by intestinal tumor suppressor CDX2 in colon cancer cells