Role of Bile Acid-induced Fibroblast Growth Factor 19 Expression in Hepatocellular Carcinoma Cell Proliferation

Abstract

Background: Fibroblast growth factor 19 (FGF19) is produced by enterocytes and acts on FGF receptor 4 (FGFR4) to down-regulate cholesterol 7α-hydroxylase (CYP7A1), the key gene involved in bile acid synthesis. Abundant bile acid increases the production of FGF19, resulting in a negative feedback cycle for bile synthesis. We hypothesized that bile acid-induced FGF19 expression also may promote hepatocellular carcinoma (HCC) cell proliferation. Methods: Huh-BAT and SNU761 HCC cell lines were treated with control small interfering RNA (siRNA) or FGF19-specific siRNA with or without chenodeoxycholic acid (CDCA, bile acid) or obeticholic acid (OCA). Cell viability, gene expression, and protein expression were assessed by MTS cell proliferation assay, RT-qPCR, and immunoblotting. Results: HCC cells treated with 25 μM CDCA exhibited increased cell proliferation and elevated levels of FGF19 mRNA. Cell transfection with FGF19- or FGFR4-specific siRNA attenuated bile acid-induced HCC cell proliferation, and FGF19-specific siRNA reduced the phosphorylation of p42/44 mitogen-activated protein kinase. These results suggest that bile acid-induced HCC cell proliferation is mediated by autocrine FGF19 signaling. Conclusions: This study demonstrated that inhibition of FGF19/FGFR4 signaling suppresses bile acid-induced HCC cell proliferation. Therefore, suppression of FGF19 or FGFR4 expression may be a therapeutic strategy for attenuating the growth of HCC with cholestasis.