Background: The clinical significance of fibroblast growth factor receptors (FGFRs) and their ligands in hepatocellular carcinoma (HCC) is extensively studied. Recently, regulation of voltage-gated sodium channels by FGFs in cancer has been reported.
Materials and methods: We investigated the relationship between FGF family genes and voltage-gated sodium channel genes (SCN) using three independent microarray and RNA-seq cohorts HCC patients. In vitro validation of 100 tissues of HCC patients with 50 control samples was performed. Statistical validation included the Wilcoxon test, Mann-Whitney U-test, correlation, Kaplan-Meier survival, and univariate and multivariate Cox regression survival analyses.
Result: The initial analysis of intracrine FGF (iFGF) ligands showed dysregulation of iFGF genes in HCC with strong association with each other in all datasets. According to in vitro analysis, overexpression of FGF14 was also observed in HCC patients suggesting potential role of FGF14 in HCC.Furthermore, network analysis showed that FGF14 was strongly interacting with SCN genes. Interestingly, SCN genes were also found in HCC samples with a positive correlation with FGF14 expression. The clinical analysis showed that FGF14, SCN2A and SCN11A are significantly associated with better disease-free survival, whereas multivariate regression analysis showed SCN11A as an independent predictor of disease-free survival in HCC patients.
Conclusion: The dysregulation of FGF14 and SCN family genes suggests a new molecular mechanism in the regulation of HCC. Furthermore, SCN11A was identified as a possible predictor for disease-free survival in HCC. Investigating these gene families using clinical studies may lead to new therapeutic approaches for HCC treatment.
Keywords: FGF14; HCC; SCN genes; SCN11A; SCN2A.