TGF-β1 Promotes Hepatocellular Carcinoma Invasion and Metastasis via ERK Pathway-Mediated FGFR4 Expression

Cell Physiol Biochem. 2018;45(4):1690-1699. doi: 10.1159/000487737. Epub 2018 Feb 22.

Abstract

Background/aims: TGF-β1 is beneficial during early liver disease but is tumor-progressive during late stages especially for hepatocellular carcinoma (HCC). Thus, exploring the underlying mechanisms may provide information about a potentially therapeutic role of TGF-β1 in HCC.

Methods: Western blot and real-time quantitative PCR were used to quantify FGFR4 expression in HCC cell lines and a normal liver cell line. After constructing the best silencing FGFR4 expression vector, migration and invasiveness of TGF-β1 in HCC was studied in vitro and in vivo. Western blot was used to study the mechanism of TGF-β1 induction on FGFR4 expression with various inhibitors.

Results: HepG2 cell lines had the most FGFR4 expression, and data show that silencing FGFR4 suppressed cell proliferation, invasion and migration in HCC induced by TGF-β1 in vitro and in vivo. Moreover, TGF-β1 induced FGFR4 expression through the ERK pathway.

Conclusion: Promoting FGFR4 expression via the ERK pathway, TGF-β1 contributes to HCC invasion and metastasis.

Keywords: ERK; FGFR4; Hepatocellular carcinoma; Invasion; Tgf-β1.

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Hep G2 Cells
  • Humans
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • MAP Kinase Signaling System / drug effects*
  • Mice
  • Mice, Nude
  • MicroRNAs / metabolism
  • Neoplasm Metastasis
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Receptor, Fibroblast Growth Factor, Type 4 / antagonists & inhibitors
  • Receptor, Fibroblast Growth Factor, Type 4 / genetics
  • Receptor, Fibroblast Growth Factor, Type 4 / metabolism*
  • Sequence Analysis, DNA
  • Smad2 Protein / antagonists & inhibitors
  • Smad2 Protein / genetics
  • Smad2 Protein / metabolism
  • Smad4 Protein / antagonists & inhibitors
  • Smad4 Protein / genetics
  • Smad4 Protein / metabolism
  • Transforming Growth Factor beta1 / pharmacology*
  • Transplantation, Heterologous

Substances

  • MicroRNAs
  • RNA, Small Interfering
  • Smad2 Protein
  • Smad4 Protein
  • Transforming Growth Factor beta1
  • FGFR4 protein, human
  • Receptor, Fibroblast Growth Factor, Type 4