Inhibition of tumor-stromal interaction through HGF/Met signaling by valproic acid

Yohsuke Matsumoto, Takahiro Motoki, Satoshi Kubota, Masaharu Takigawa, Hirohito Tsubouchi, Eiichi Gohda

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)


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 E2 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.

Original languageEnglish
Pages (from-to)110-116
Number of pages7
JournalBiochemical and Biophysical Research Communications
Issue number1
Publication statusPublished - Feb 1 2008


  • Butyric acid
  • Dermal fibroblast
  • Hepatocyte growth factor
  • Histone deacetylase inhibitor
  • Induction
  • Trichostatin A
  • Tumor invasion
  • Valproic acid

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology


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