Caudal-related homeobox
transcription factor 2 (CDX2), an intestine-specific nuclear
transcription factor, has been strongly implicated in the tumourigenesis of various human
cancers. However, the functional role of CDX2 in the development and progression of
colorectal cancer (CRC) is not well known. In this study, CDX2 knockdown in
colon cancer cells promoted cell proliferation in vitro, accelerated
tumor formation in vivo, and induced a cell cycle transition from G0/G1 to S phase, whereas CDX2 overexpression inhibited cell proliferation. TOP/FOP-Flash reporter assay showed that CDX2 knockdown or CDX2 overexpression significantly increased or decreased Wnt signaling activity. Western blot assay showed that downstream targets of Wnt signaling, including β-
catenin,
cyclin D1 and c-myc, were up-regulated or down-regulated in CDX2-knockdown or CDX2-overexpressing
colon cancer cells. In addition, suppression of Wnt signaling by
XAV-939 led to a marked suppression of the cell proliferation enhanced by CDX2 knockdown, whereas activation of this signaling by
CHIR-99021 significantly enhanced the cell proliferation inhibited by CDX2 overexpression. Dual-
luciferase reporter and quantitative
chromatin immunoprecipitation (qChIP) assays further confirmed that CDX2 transcriptionally activates
glycogen synthase kinase-3β (GSK-3β) and axis inhibition
protein 2 (Axin2) expression by directly binding to the promoter of GSK-3β and the upstream enhancer of Axin2. In conclusion, these results indicated that CDX2 inhibits the proliferation and
tumor formation of
colon cancer cells by suppressing Wnt/β-
catenin signaling.