The phenotype of Maid KO mice is normal. We therefore added 3 month repeated CCl4 injection (0.5mg/kg body) into Maid KO mice and wild type mice, and then analyzed liver fibrosis and hepatocarcinogenesis. We did DNA chip analysis and Ingenuity pathway analysis using 3 month CCl4 injected Maid KO and wild type livers and control no damage. We used 20 nM Bortezomib on HepG2 cells and human hepatocytes, and analyzed cell proliferation and HHM Selleckchem Z VAD FMK expression. (Results) CCl4 injected Maid KO mice accelerated to induce liver fibrosis compared with wild type mice (p<0.05), and had AFP positive-HCC (25%).

DNA chip analysis revealed that “”Cell cycle”" related genes such as Cyclin A2, Cyclin E1, Cyclin B and CDC25c were increased. We also found that these genes related with “”double strand DNA break repair”" such as RAD51, RAD54L and RAD50 were also increased. DNA repair genes such as BLM, MSH2, MHH1, RAD50 and MRE1 1 were also activated in Maid KO livers. Moreover, we found that TGF-beta 3, Collagen 1A Neratinib chemical structure and Collagen 3A were significantly increased. In vitro analysis, Bortezomib

specifically inhibited HepG2-proliferation with up-regulated HHM expression. (Discussion) We found that Maid KO mice itself activated DNA damage related and cell cycle related genes. Concerning with TGF-beta signaling, Maid disruption does not stop TGF-beta related cell inhibition and ECM production. From these systems, Maid KO mice induced both liver fibrosis and generation of HCC. Bortezomib induced HHM expression with inhibition of cell proliferation in HepG2 but not hepatocyte. These results indicated that Maid specifically 上海皓元医药股份有限公司 regulate DNA damage and progression of liver fibrosis and hepatocarcinogenesis. (Conclusion) Maid is a specific guardian gene to regulate DNA damage in liver fibrosis and hepatocarcinogenesis. Disclosures: Tomoaki Murata – Board Membership: Naoki Yamamoto, Taro

Takami, Issei Saeki, Koichi Fujisawa, Hiroshi Nishina, Isao Sakaida; Speaking and Teaching: Shuji Terai The following people have nothing to disclose: Shuji Terai, Naoki Yamamoto, Taro Takami, Issei Saeki, Koichi Fujisawa, Hiroshi Nishina, Isao Sakaida Tivantinib has been tested in clinical trials as c-MET inhibitor and demonstrated clinical benefit as a second line treatment of hepatocellular carcinoma (HCC). Since its efficacy was predicted by elevated expression of c-MET in previous phase-2 and -3 randomized trials, a phase-3 trial in HCC patients selected according to c-MET expression has been initiated. Unexpectedly, recent in vitro studies challenged the notion of tivantinib as a selective c-MET inhibitor. To provide a possible explanation for these conflicting data, we investigated the molecular mechanisms of action of tivantinib and whether their regulation is influenced by c-MET by using a panel of 8 cell lines showing different c-MET expression status.