FGF9 Recruits β‐Catenin to Increase Hepatic ECM Synthesis and Promote NASH‐Driven HCC

Abstract

AbstractMost nonalcoholic steatohepatitis (NASH) patients develop severe fibrosis through extracellular matrix (ECM) accumulation, which can lead to hepatocellular carcinoma (HCC). Fibroblast growth factor 9 (FGF9) is involved in serial types of cancer; however, the specific role of FGF9 in NASH‐driven HCC is not fully understood. This study finds that FGF9 is increased in patients with NASH‐associated HCC. Furthermore, NASH‐driven HCC mice models by feeding wildtype mice with high‐fat/high‐cholesterol (HFHC) diet and low dose carbon tetrachloride (CCl4) treatment is established; and identified that hepatic FGF9 is increased; with severe fibrosis. Additionally, AAV‐mediated knockdown of FGF9 reduced the hepatic tumor burden of NASH‐driven HCC mice models. Hepatocyte‐specific FGF9 transgenic mice (FGF9Alb) fed with a HFHC diet without CCl4 treatment exhibited an increased hepatic ECM and tumor burden. However, XAV‐939 treatment blocked ECM accumulation and NASH‐driven HCC in FGF9Alb mice fed with HFHC diet. Molecular mechanism studies show that FGF9 stimulated the expression of ECM related genes in a β‐catenin dependent manner; and FGF9 exerts its effect on β‐catenin stability via the ERK1/2‐GSK‐3β signaling pathway. In summary, the data provides evidence for the critical role of FGF9 in NASH‐driven HCC pathogenesis; wherein it promotes the tumors formation through the ECM pathway.