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Hepatocyte growth factor promotes hepatocarcinogenesis through c-Met autocrine activation and enhanced angiogenesis in transgenic mice treated with diethylnitrosamine

Oncogene volume 21, pages 1791–1799 (2002)Cite this article

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.

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Abbreviations

HGF:

hepatocyte growth factor

DEN:

diethylnitrosamine

HCC:

hepatocellular carcinoma

VEGF:

vascular endothelial growth factor

MT:

metallothionein

d-HGF:

5 amino acid deleted isoform of HGF

vWF:

von-Willebrand Factor

TGF-α:

transforming growth factor alpha

EGFR:

epidermal growth factor receptor

H&E:

hematoxylin and eosin

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

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Acknowledgements

The authors thank Dr William J LaRochelle from CuraGen Corporation (New Haven, CT, USA), for providing clone LA 737. We are indebted to Dr Hiromi Sakata for critical reading of this manuscript. This work was supported in part by a Grant-in Aid for Scientific Research (No.11680817) from the Ministry of Education, Science, Sports and Culture of the Japanese Government.

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Authors and Affiliations

  1. The First Department of Internal Medicine, Gunma University School of Medicine, Maebashi, Gunma 371-8511, Japan

    Norio Horiguchi, Hisashi Takayama, Mitsuo Toyoda, Toshiyuki Otsuka, Hitoshi Takagi & Masatomo Mori

  2. Division of Diagnostic Pathology, Gunma University School of Medicine, Maebashi, Gunma 371-8511, Japan

    Toshio Fukusato

  3. Laboratory of Molecular Biology, National Cancer Institute, Bethesda, 20892-4255, Maryland, MD, USA

    Glenn Merlino

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Correspondence to Hitoshi Takagi.

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Horiguchi, N., Takayama, H., Toyoda, M. et al. Hepatocyte growth factor promotes hepatocarcinogenesis through c-Met autocrine activation and enhanced angiogenesis in transgenic mice treated with diethylnitrosamine. Oncogene 21, 1791–1799 (2002). https://doi.org/10.1038/sj.onc.1205248

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