Expression of fibroblast growth factor receptors in hepatocellular carcinoma

Fibroblast growth factor receptors (FGFRs) are generated from four genes (FGFR1/2/3/4). Alternative splicing of FGFR1-3 creates b- and c-isoforms that differ in ligand-binding and thus further enhance the complexity of FGF-signalling. FGFR-inhibition has been shown to inhibit progression of hepatocellular carcinoma (HCC) in experimental models. However, existing clinical studies with mostly unspecific FGFR-pan-inhibitors in non-selected patient-cohorts have not shown beneficial effects on survival.

The aim of this study was to gain insights into the expression of different FGFR-variants in HCC.

Methods and Results COSMIC database analysis revealed that genetic FGFR-aberrations are rare in HCC (less than 4% in 2090 patients). Still, FGFR1, FGFR3 and FGFR4 are upregulated in human HCC-cell-lines compared to primary human hepatocytes and most HCC-tissues compared to corresponding non-tumorous liver. Expression of different FGFRs significantly correlated with each other pointing to common transcriptional regulation. In search for the molecular mechanisms, we analyzed histone acetylation and identified histone deacetylase 7 (HDAC7) as negative regulator of FGFR-expression in HCC-cells. Regarding variant-specific FGFR-expression, we analyzed the effects of siRNA-mediated knockdown of epithelial splicing regulatory protein 1 (ESRP1) in HCC-cells. ESRP1-suppression led to significant upregulation of FGFR2c and FGFR3c but downregulation of the corresponding b-isoforms. Surprisingly, ESRP1-knockdown significantly inhibited expression of both FGFR1b and FGFR1c.

Summary and conclusion Our study provides novel insights into the transcriptional regulation of FGFR-variants in HCC that might be exploited for new therapeutic strategies or prognostic parameters. The observed variation in the FGFR-expression pattern might also be utilized for individualized FGFR-inhibitory strategies.

Publication History

Article published online:
26 January 2022