Hepatocyte growth factor promotes hepatocarcinogenesis through c-Met autocrine activation and enhanced angiogenesis in transgenic mice treated with diethylnitrosamine.
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.
Horiguchi
Norio
N
The First Department of Internal Medicine, Gunma University School of Medicine, Maebashi, Gunma 371-8511, Japan.
Takayama
Hisashi
H
Toyoda
Mitsuo
M
Otsuka
Toshiyuki
T
Fukusato
Toshio
T
Merlino
Glenn
G
Takagi
Hitoshi
H
Mori
Masatomo
M
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
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