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

Wnt signalling is often constitutively active in colorectal cancer cells. The expression of the intestinal specific transcription factor CDX2 is found transiently decreased in invasive cells at the tumor/stroma interface. A recent ChIP-Seq study has indicated that several Wnt signalling-related genes are regulated by CDX2. The aim was to investigate the role of decreased CDX2 level on the expression of APC, AXIN2 and GSK3β in migrating colon cancer cells at the invasive front. CDX2 bound promoter and enhancer regions from APC, AXIN2 and GSK3β were analysed 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 activated APC and AXIN2 promoter activity via intestinal cell-specific enhancer elements. Suppressed CDX2 expression was associated with endogenous down-regulation of APC and AXIN2 expression in Caco-2 cells but did not effect GSK3β expression. Furthermore, elevated levels of nuclear β-catenin and reduced levels of cytoplasmic APC were correlated to a low CDX2 expression in migrating colon cancer cells in vivo. These results suggest that a low CDX2 level has influence on the Wnt signalling in invasive colon cancer cells possibly promoting cellular migration.