Changes in hepatic Wnt and frizzled expression profile during hepatocellular carcinoma development in Farnesoid X receptor knockout mice.

Farnesoid X‐receptor (FXR), the main bile acid sensing receptor of the body, is also known to have anti‐tumorigenic properties. It is known that FXR knockout (FXR‐KO) mice develop spontaneous hepatocellular carcinoma (HCC). We have previously shown that increase in β‐catenin activation via canonical Wnt pathway is associated with the HCC development in FXR‐KO mice. We observed increased GSK‐3β inactivation and increased Disheveled expression in the FXR‐KO mice over a time course of 3 to 15 months. To determine if the increase GSK3β inactivation is driven by specific changes in Wnt and its receptor Frizzled (Fzl) expression, we quantified mRNA for 16 Wnt and 11 Fzl genes in the livers of wild type (WT) and FXR‐KO mice obtained at 8 months (precancerous) and 15 months (tumor bearing) of age. The data show an increase in the expression of 7 out of 10 Fzls (Fzd1, Fzd2, Fzd4, Fzd5, Fzd7, Fzd8, and Fzd9) and 4 out of 16 Wnts (Wnt4, Wnt5a, Wnt5b, and Wnt9b) in FXR‐KO mice as compared to WT mice. Western blot analysis corroborated the mRNA data. These data indicate that β‐catenin activation observed in HCC of FXR‐KO mice could be due to increased Wnt secretion in the FXR‐KO mice. These data suggest a complex interaction between FXR and Wnt/β‐catenin signaling in the liver is involved in pathogenesis of HCC.