Inhibition of tumor-stromal interaction through HGF/Met signaling by valproic acid |
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Authors: | Matsumoto Yohsuke Motoki Takahiro Kubota Satoshi Takigawa Masaharu Tsubouchi Hirohito Gohda Eiichi |
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Affiliation: | a Department of Immunochemistry, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1, Tsushima-naka, Okayama 700-8530, Japan b Department of Biochemistry and Molecular Dentistry, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Shikata-cho, Okayama 700-8525, Japan c Digestive Disease and Life-style Related Disease, Health Research Human and Environmental Sciences, Kagoshima University, Graduate School of Medicine and Dental Sciences, Sakuragaoka, Kagoshima 890-8520, Japan |
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Abstract: | 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. |
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Keywords: | Hepatocyte growth factor Valproic acid Histone deacetylase inhibitor Butyric acid Trichostatin A Induction Tumor invasion Dermal fibroblast |
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