title: Hepatocyte growth factor promotes hepatocarcinogenesis through c-Met autocrine activation and enhanced angiogenesis in transgenic mice treated with diethylnitrosamine.
abstract: Hepatocyte growth factor (HGF) is a mitogen for hepatocytes, but it is not clear whether HGF stimulates or inhibits hepatocarcinogenesis. We previously reported that HGF transgenic mice under the metallothionein gene promoter developed benign and malignant liver tumors spontaneously after 17 months of age. To elucidate the role of HGF in hepatocarcinogenesis, diethylnitrosamine (DEN) was administered to HGF transgenic mice. HGF overexpression accelerated DEN-induced hepatocarcinogenesis, often accompanied by abnormal blood vessel formation. In this study, 59% of transgenic males (versus 20% of wild-type males) and 39% of transgenic females (versus 2% of wild-type females) developed either benign or malignant liver tumors by 48 weeks (P<0.005, P<0.001, respectively). Moreover, 33% of males and 23% of female transgenic mice developed hepatocellular carcinoma (HCC), while none of the wild-type mice developed HCC (P<0.001, P<0.005, respectively). Enhanced kinase activity of the HGF receptor, Met, was detected in most of these tumors. Expression of vascular endothelial growth factor (VEGF) was up-regulated in parallel with HGF transgene expression. Taken together, our results suggest that HGF promotes hepatocarcinogenesis through the autocrine activation of the HGF-Met signaling pathway in association with stimulation of angiogenesis by HGF itself and/or indirectly through VEGF.
authors.affiliation: The First Department of Internal Medicine, Gunma University School of Medicine, Maebashi, Gunma 371-8511, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Horiguchi
authors.forename: Hisashi
authors.initials: H
authors.lastname: Takayama
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Toyoda
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Otsuka
authors.forename: Toshio
authors.initials: T
authors.lastname: Fukusato
authors.forename: Glenn
authors.initials: G
authors.lastname: Merlino
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takagi
authors.forename: Masatomo
authors.initials: M
authors.lastname: Mori
mesh_terms: D000477:Alkylating Agents; D000818:Animals; D019898:Autocrine Communication / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D004052:Diethylnitrosamine; D016228:Endothelial Growth Factors / Q000378:metabolism; D005260:Female; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D007124:Immunoenzyme Techniques; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008222:Lymphokines / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D012313:RNA / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D000477:Alkylating Agents; D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D004052:Diethylnitrosamine; D012313:RNA; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met