| セッション情報 |
International Forum 2(Liver) 1.Pathogenesis and Epidemiology
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| タイトル |
IF2-1-IV (Plenary presentation) Loss of hepatocyte growth factor/c-met signaling pathway accelerates early stages of DEN-induced hepatocarcinogenesis
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| 演者 |
Taro Takami（Department of Molecular Science and Applied Medicine(Gastroenterology and Hepatology)Yamaguchi University School of MedicineUbeJapan^1） |
| 共同演者 |
Koichi Uchida（Department of Molecular Science and Applied Medicine(Gastroenterology and Hepatology)Yamaguchi University School of MedicineUbeJapan^1）, Shoji Terai（Department of Molecular Science and Applied Medicine(Gastroenterology and Hepatology)Yamaguchi University School of MedicineUbeJapan^1）, Valentina M.Factor（Laboratory of Experimental Carcinogenesis(LEC)NCINIHUSA^2）, Isao Sakaida（Department of Molecular Science and Applied Medicine(Gastroenterology and Hepatology)Yamaguchi University School of MedicineUbeJapan^1）, Snorri S.Thorgeirsson（Laboratory of Experimental Carcinogenesis(LEC)NCINIHUSA^2） |
| 抄録 |
HGF has been reported to have both positive and negative effects on carcinogenesis． And possible involve－ment of chronic oxidative stress in hepatocarcinogenesis has been also reported． Herewe show that theloss of c－Met signaling in hepatocytes promoted a state of chronic oxidative stress and enhanced ratherthan suppressed the early stages of chemical hepatocarcinogenesis． c－Met conditional knockout mice （c一御θ押AlbCre＋／一；MetLivKO）treated with N－nitrosodiethylamine（DEN）developed significantly moreand bigger tumors and with a shorter latency as compared with control （wt／wtAlbCre’／一 ； Cre－Ctrl）mice． Accelerated tumor development was associated with increased rate of cell proliferation and pro－longed activation of epidermal growth factor receptor （EGFR） sigrialing． MetLivKO livers treated withDEN also displayed elevated lipid peroxidationdecreased ratio of reduced glutathione （GSH） to oxidizedglutathione（GSSG）and up－regulation of Superoxide dismutase 1（Sod1）and且eat shock protein 70（Hsp70）all consistent with increased oxidative stress． Likewisegene expression profiling performed at 3 and5 months after DEN treatment revealed up－regulation of genes associated with cell proliferation andstress responses in c－Met mutant livers． The negative effects of c－Met－deficiency were reversed bychronic oral administration of anti－oxidant N－acetylcysteine （NAC）． NAC blocked the EGFR activationand reduced the DEN－initiated hepatocarcinogenesis to the levels of Cre－Ctrl mice． These results suggestthat intact HGF／e－Met signaling is essential for maintaining normal redox homeostasis in the liver andhas tumor suppressor effect （s） during the early stages of DEN－induced hepatocarcinogenesis． |
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