Farnesoid X Receptor (FXR), the primary bile acid sensing nuclear receptor is also known for its anti-cancer properties. It is known that FXR deficiency in mice (FRX-KO) results in spontaneous hepatocellular carcinoma (HCC) but the mechanisms are not completely understood. Here we report that sustained activation of Wnt/β-catenin pathway is associated with spontaneous HCC in FXR-KO mice. HCC development was studied in FXR-KO mice at 3, 8 and 14 months of age. No tumors were observed at either 3 or 8 months but presence of HCC was observed in 100% of the FXR-KO mice at the age of 14 months. Further analysis revealed no change in β-catenin activation in the livers of 3-month-old FXR-KO mice but a moderate increase was observed in 8-month-old FXR-KO mice. β-Catenin activation further increased significantly in 14-month-old tumor bearing mice. Further analysis revealed two independent mechanisms might be involved in β-catenin activation in the FXR-KO livers. Activation of canonical Wnt signaling was evident as indicated by increased Wnt4 and dishevelled (Dvl) expression along with GSK-3β inactivation. We also observed decreased expression of E-cadherin, a known regulator of β-catenin, in FXR-KO mice. The decrease in E-cadherin expression was accompanied by increased expression of its transcriptional repressor, Snail. Consistent with the increased HCC in FXR-KO mice we observed significant decrease in FXR expression and activity in human HCC samples. Taken together, these data indicate that temporal increase in activation of Wnt/β-catenin is observed during spontaneous HCC development in FXR-KO mice and is potentially critical for tumor development.
- Received January 13, 2011.
- Revision received March 22, 2011.
- Accepted March 23, 2011.
- The American Society for Pharmacology and Experimental Therapeutics