Effects and mechanism of the bile acid (farnesoid X) receptor on the Wnt/β-catenin signaling pathway in colon cancer.

The downregulation of farnesoid X receptor (FXR; gene name, nuclear receptor subfamily 1 group h member 4), an enteric nuclear bile acid receptor, has been reported in colorectal carcinoma (CRC), and FXR expression has been inversely correlated with CRC stage and clinical outcome. FXR knockdown in chronic colitis mouse models of intestinal tumorigenesis results in early mortality and increased tumor progression via promoting Wnt signaling. The aim of the present study was to explore the effects and mechanism of FXR on the Wnt/beta-catenin signal pathway in CRC. FXR and beta-catenin protein expression levels were detected in an ulcerative colitis mouse model and human colon cancer cell lines (HT-29, Caco-2 and HCT-116). Gain- and loss-of-function studies were conducted by transfecting colon cancer cells with FXR siRNA and treating them with the FXR agonist GW4064. Subsequently, beta-catenin transcriptional activity was measured using the dual-luciferase assay, and beta-catenin/TCF4 complex levels and beta-catenin protein and mRNA expression levels were determined. FXR and beta-catenin expression levels were inversely associated in both the animal model and colon cancer cells. The Wnt signaling pathway was activated by increased beta-catenin/TCF4 complex levels upon FXR silencing; however, mRNA and protein levels of beta-catenin were not significantly affected. The FXR agonist GW4064 significantly inhibited the proliferation of cells but promoted the transcriptional activity of beta-catenin. Thus, the present study demonstrated that FXR influences the Wnt/beta-catenin signaling pathway. Furthermore, loss of FXR expression promotes the transcriptional activity of beta-catenin, whereas FXR activation results in the opposite effect.