FGF19 and FGFR4 promotes the progression of gallbladder carcinoma in an autocrine pathway dependent on GPBAR1-cAMP-EGR1 axis.

Abstract

Treatment options for gallbladder carcinoma (GBC) are limited and GBC prognosis remains poor. There is no well-accepted targeted therapy to date, so effective biomarkers of GBC are urgently needed. Here we investigated the expression and correlations of fibroblast growth factor receptors (FGFR1-4) and 18 fibroblast growth factors (FGFs) in two independent patient cohorts and evaluated their prognostic significance. Consequently, we demonstrated that both FGF19 and FGFR4 were unfavorable prognostic biomarkers, and their co-expression was a more sensitive predictor. By analyzing the correlations between all 18 FGFs and FGFR4, we showed that FGF19 expression was significantly associated with FGFR4 and promoted GBC progression via stimulating FGFR4. With experiments using GBC cells, GPBAR1-/- mice models, and human subjects, we demonstrated that elevated bile acids (BAs) could increase the transcription and expression of FGF19 and FGFR4 by activating GPBAR1-cAMP-EGR1 pathway. FGF19 secreted from GBC cells promoted GBC progression by stimulating FGFR4 and downstream ERK in an autocrine manner with bile as a potential carrier. Patients with GBC had significantly higher FGF19 in serum and bile, compared to patients with cholelithiasis. BLU9931 inhibited FGFR4 and attenuated its oncogenic effects in GBC cell line. In conclusion, upregulation of BAs elevated co-expression of FGF19 and FGFR4 by activating GPBAR1-cAMP-EGR1 pathway. Co-expression of FGF19 and FGFR4 was a sensitive and unfavorable prognostic marker. GBC cells secreted FGF19 and facilitated progression by activating FGFR4 with bile as a potential carrier in an autocrine pathway.