Inhibition of Tumor-Stromal Interaction Through HGF/Met Signaling by Valproic Acid

Biochem Biophys Res Commun. 2008 Feb 1;366(1):110-6. doi: 10.1016/j.bbrc.2007.11.089. Epub 2007 Nov 29.


Hepatocyte growth factor (HGF), which is produced by surrounding stromal cells, including fibroblasts and endothelial cells, has been shown to be a significant factor responsible for cancer cell invasion mediated by tumor-stromal interactions. We found in this study that the anti-tumor agent valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, strongly inhibited tumor-stromal interaction. VPA inhibited HGF production in fibroblasts induced by epidermal growth factor (EGF), platelet-derived growth factor, basic fibroblast growth factor, phorbol 12-myristate 13-acetate (PMA) and prostaglandin E(2) without any appreciable cytotoxic effect. Other HDAC inhibitors, including butyric acid and trichostatin A (TSA), showed similar inhibitory effects on HGF production stimulated by various inducers. Up-regulations of HGF gene expression induced by PMA and EGF were also suppressed by VPA and TSA. Furthermore, VPA significantly inhibited HGF-induced invasion of HepG2 hepatocellular carcinoma cells. VPA, however, did not affect the increases in phosphorylation of MAPK and Akt in HGF-treated HepG2 cells. These results demonstrated that VPA inhibited two critical processes of tumor-stromal interaction, induction of fibroblastic HGF production and HGF-induced invasion of HepG2 cells, and suggest that those activities serve for other anti-tumor mechanisms of VPA besides causing proliferation arrest, differentiation, and/or apoptosis of tumor cells.

MeSH terms

  • Carcinoma, Hepatocellular / metabolism*
  • Cell Communication / drug effects*
  • Cell Line
  • Dose-Response Relationship, Drug
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism*
  • Hepatocyte Growth Factor / metabolism*
  • Humans
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-met
  • Receptors, Growth Factor / metabolism*
  • Signal Transduction / drug effects
  • Stromal Cells / metabolism*
  • Valproic Acid / administration & dosage*


  • Proto-Oncogene Proteins
  • Receptors, Growth Factor
  • Valproic Acid
  • Hepatocyte Growth Factor
  • MET protein, human
  • Proto-Oncogene Proteins c-met