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The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice

Nature Medicine volume 4, pages 1065–1067 (1998)Cite this article

Abstract

Hepatitis C virus (HCV) is the main cause of chronic hepatitis worldwide. Chronic hepatitis ultimately results in the development of hepatocellular carcinoma1,2 (HCC). However, the mechanism of hepatocarcinogenesis in chronic HCV infection is still unclear. The ability of the core protein of HCV to modulate gene transcription, cell proliferation and cell death3,4,5,6,7,8 may be involved in the pathogenesis of HCC. Here, we report the development of HCC in two independent lines of mice transgenic for the HCV core gene, which develop hepatic steatosis early in life as a histological feature characteristic of chronic hepatitis C ( ref. 9 ). After the age of 16 months, mice of both lines developed hepatic tumors that first appeared as adenomas containing fat droplets in the cytoplasm. Then HCC, a more poorly-differentiated neoplasia, developed from within the adenomas, presenting in a 'nodule-in-nodule' manner without cytoplasmic fat droplets; this closely resembled the histopathological characteristics of the early stage of HCC in patients with chronic hepatitis C (refs. 10,11 ). These results indicate that the HCV core protein has a chief role in the development of HCC, and that these transgenic mice provide good animal models for determining the molecular events in hepatocarcinogenesis with HCV infection.

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Figure 1: Hepatitis C virus core gene transgenic mice: Transgene construct and expression.
Figure 2: Pathological changes in the liver of HCV core transgenic mice.

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Acknowledgements

We thank K. Suzuki for excellent electron microscopy and C. Ariga for technical assistance. This work was supported in part by a Grant-in-Aid from the Ministry of Education, Science and Culture of Japan and grants from The Sankyo Foundation of Life Science and The Mochida Memorial Foundation for Medical and Pharmaceutical Research.

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Authors and Affiliations

  1. First Department of Internal Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo , 113-8655

    Kyoji Moriya, Hajime Fujie, Yoshizumi Shintani, Hiroshi Yotsuyanagi, Takeya Tsutsumi, Satoshi Kimura & Kazuhiko Koike

  2. Daiichi Pharmaceuticals,, 1-16-13 Kitakasai , Edogawa-ku, Tokyo, 134-8630

    Kotaro Ishibashi

  3. Department of Virology II,National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan

    Yoshiharu Matsuura & Tatsuo Miyamura

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  1. Kyoji Moriya
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Correspondence to Kazuhiko Koike.

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Moriya, K., Fujie, H., Shintani, Y. et al. The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice. Nat Med 4, 1065–1067 (1998). https://doi.org/10.1038/2053

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