Fibroblast Growth Factor 9 is expressed by activated hepatic stellate cells and promotes progression of hepatocellular carcinoma

The fibroblast growth factor (FGF) family comprises 22 proteins. FGFs can be divided into seven subfamilies and are classified into paracrine, intracrine and endocrine factors. FGFs play a major role in embryonic development, differentiation and wound healing. Liver fibrosis can be considered as chronic wound healing response, and hepatocellular carcinoma (HCC) frequently develops in this wound "that never heals". The activation of hepatic stellate cells (HSC) is a key event of hepatic fibrosis and activated HSC are known to promote HCC progression, however, the role of different FGFs in HCC is largely unknown.

The aim of this study was to identify FGFs that are expressed by HSC and affect HCC progression.

Methods and Results:

First, we screened for FGFs that increased during in vitro activation of human HSC and in different murine models of hepatic fibrosis; a further criterion was significant correlation with markers of activated HSC (collagen I and alpha-smooth muscle actin expression) in liver tissues of patients with different types of chronic liver disease. FGF-1/2, FGF-5, FGF-7/10 and FGF-9 fulfilled these criteria. In subsequent analysis, we focused on FGF-9, and found that its expression was almost undetectable in different human HCC cell lines (Hep3B, HepG2, Huh7, PLC) compared with activated HSCs. Fitting to this, FGF9 expression correlated significantly with collagen expression in human HCC tissues. Importantly, TCGA (The Cancer Genome Atlas) data set analysis of 381 HCC patients revealed that high FGF9 expression in HCC correlated with poor patient survival. In functional in vitro analysis, recombinant FGF9 (rFGF9) induced proliferation, colony formation and migratory activity of human HCC cell lines. Furthermore, rFGF9 inhibited etoposide-induced apoptosis of HCC cells. Moreover, rFGF9 significantly decreased the efficacy of sorafenib to inhibit proliferation and to induce cell death in HCC cells.

Summary and conclusion:

FGF9 derived from activated HSC enhances the tumorigenicity and therapy resistance of HCC cells embedded in a fibrotic microenvironment. Herewith, FGF9 appears as potential prognostic parameter and promising therapeutic target in HCC.