Abstract
Clinical evidence suggests that hepatitis C virus (HCV) is etiologically involved in hepatic cancer and liver cirrhosis. To investigate whether the HCV nonstructural protein NS3 has oncogenic activity, NIH 3T3 cells were transfected with an expression vector containing cDNA for the 5'- or 3'-half sequence of the HCV genome segment encoding NS3. Only cells transfected with the 5'-half cDNA rapidly proliferated, lost contact inhibition, grew anchorage independently in soft agar, and formed tumors in nude mice. PCR analysis confirmed the presence of the 5'-half DNA in the transfectants. These results suggest that the 5' region of the HCV genome segment encoding NS3 is involved in cell transformation.
Full Text
The Full Text of this article is available as a PDF (616.4 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Bartenschlager R., Ahlborn-Laake L., Mous J., Jacobsen H. Nonstructural protein 3 of the hepatitis C virus encodes a serine-type proteinase required for cleavage at the NS3/4 and NS4/5 junctions. J Virol. 1993 Jul;67(7):3835–3844. doi: 10.1128/jvi.67.7.3835-3844.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bazan J. F., Fletterick R. J. Detection of a trypsin-like serine protease domain in flaviviruses and pestiviruses. Virology. 1989 Aug;171(2):637–639. doi: 10.1016/0042-6822(89)90639-9. [DOI] [PubMed] [Google Scholar]
- Bukh J., Miller R. H., Kew M. C., Purcell R. H. Hepatitis C virus RNA in southern African blacks with hepatocellular carcinoma. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1848–1851. doi: 10.1073/pnas.90.5.1848. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Grakoui A., McCourt D. W., Wychowski C., Feinstone S. M., Rice C. M. Characterization of the hepatitis C virus-encoded serine proteinase: determination of proteinase-dependent polyprotein cleavage sites. J Virol. 1993 May;67(5):2832–2843. doi: 10.1128/jvi.67.5.2832-2843.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Haruna Y., Hayashi N., Hiramatsu N., Takehara T., Hagiwara H., Sasaki Y., Kasahara A., Fusamoto H., Kamada T. Detection of hepatitis C virus RNA in liver tissues by an in situ hybridization technique. J Hepatol. 1993 Apr;18(1):96–100. doi: 10.1016/s0168-8278(05)80015-7. [DOI] [PubMed] [Google Scholar]
- Hijikata M., Mizushima H., Akagi T., Mori S., Kakiuchi N., Kato N., Tanaka T., Kimura K., Shimotohno K. Two distinct proteinase activities required for the processing of a putative nonstructural precursor protein of hepatitis C virus. J Virol. 1993 Aug;67(8):4665–4675. doi: 10.1128/jvi.67.8.4665-4675.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hijikata M., Mizushima H., Tanji Y., Komoda Y., Hirowatari Y., Akagi T., Kato N., Kimura K., Shimotohno K. Proteolytic processing and membrane association of putative nonstructural proteins of hepatitis C virus. Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10773–10777. doi: 10.1073/pnas.90.22.10773. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ishihama A., Nagata K. Viral RNA polymerases. CRC Crit Rev Biochem. 1988;23(1):27–76. doi: 10.3109/10409238809103119. [DOI] [PubMed] [Google Scholar]
- Kato N., Hijikata M., Ootsuyama Y., Nakagawa M., Ohkoshi S., Sugimura T., Shimotohno K. Molecular cloning of the human hepatitis C virus genome from Japanese patients with non-A, non-B hepatitis. Proc Natl Acad Sci U S A. 1990 Dec;87(24):9524–9528. doi: 10.1073/pnas.87.24.9524. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kumatori A., Tanaka K., Inamura N., Sone S., Ogura T., Matsumoto T., Tachikawa T., Shin S., Ichihara A. Abnormally high expression of proteasomes in human leukemic cells. Proc Natl Acad Sci U S A. 1990 Sep;87(18):7071–7075. doi: 10.1073/pnas.87.18.7071. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kuo G., Choo Q. L., Alter H. J., Gitnick G. L., Redeker A. G., Purcell R. H., Miyamura T., Dienstag J. L., Alter M. J., Stevens C. E. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science. 1989 Apr 21;244(4902):362–364. doi: 10.1126/science.2496467. [DOI] [PubMed] [Google Scholar]
- Manabe S., Fuke I., Tanishita O., Kaji C., Gomi Y., Yoshida S., Mori C., Takamizawa A., Yosida I., Okayama H. Production of nonstructural proteins of hepatitis C virus requires a putative viral protease encoded by NS3. Virology. 1994 Feb;198(2):636–644. doi: 10.1006/viro.1994.1075. [DOI] [PubMed] [Google Scholar]
- Mangia A., Vallari D. S., Di Bisceglie A. M. Use of confirmatory assays for diagnosis of hepatitis C viral infection in patients with hepatocellular carcinoma. J Med Virol. 1994 Jun;43(2):125–128. doi: 10.1002/jmv.1890430205. [DOI] [PubMed] [Google Scholar]
- Rechsteiner M. Natural substrates of the ubiquitin proteolytic pathway. Cell. 1991 Aug 23;66(4):615–618. doi: 10.1016/0092-8674(91)90104-7. [DOI] [PubMed] [Google Scholar]
- Rice C. M., Lenches E. M., Eddy S. R., Shin S. J., Sheets R. L., Strauss J. H. Nucleotide sequence of yellow fever virus: implications for flavivirus gene expression and evolution. Science. 1985 Aug 23;229(4715):726–733. doi: 10.1126/science.4023707. [DOI] [PubMed] [Google Scholar]
- Saito I., Miyamura T., Ohbayashi A., Harada H., Katayama T., Kikuchi S., Watanabe Y., Koi S., Onji M., Ohta Y. Hepatitis C virus infection is associated with the development of hepatocellular carcinoma. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6547–6549. doi: 10.1073/pnas.87.17.6547. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sherker A. H., Marion P. L. Hepadnaviruses and hepatocellular carcinoma. Annu Rev Microbiol. 1991;45:475–507. doi: 10.1146/annurev.mi.45.100191.002355. [DOI] [PubMed] [Google Scholar]
- Stanton V. P., Jr, Nichols D. W., Laudano A. P., Cooper G. M. Definition of the human raf amino-terminal regulatory region by deletion mutagenesis. Mol Cell Biol. 1989 Feb;9(2):639–647. doi: 10.1128/mcb.9.2.639. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Suzich J. A., Tamura J. K., Palmer-Hill F., Warrener P., Grakoui A., Rice C. M., Feinstone S. M., Collett M. S. Hepatitis C virus NS3 protein polynucleotide-stimulated nucleoside triphosphatase and comparison with the related pestivirus and flavivirus enzymes. J Virol. 1993 Oct;67(10):6152–6158. doi: 10.1128/jvi.67.10.6152-6158.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Takada S., Koike K. X protein of hepatitis B virus resembles a serine protease inhibitor. Jpn J Cancer Res. 1990 Dec;81(12):1191–1194. doi: 10.1111/j.1349-7006.1990.tb02675.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Takamizawa A., Mori C., Fuke I., Manabe S., Murakami S., Fujita J., Onishi E., Andoh T., Yoshida I., Okayama H. Structure and organization of the hepatitis C virus genome isolated from human carriers. J Virol. 1991 Mar;65(3):1105–1113. doi: 10.1128/jvi.65.3.1105-1113.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Takegami T., Sakamuro D., Furukawa T. Japanese encephalitis virus nonstructural protein NS3 has RNA binding and ATPase activities. Virus Genes. 1995 Jan;9(2):105–112. doi: 10.1007/BF01702653. [DOI] [PubMed] [Google Scholar]
- Tomei L., Failla C., Santolini E., De Francesco R., La Monica N. NS3 is a serine protease required for processing of hepatitis C virus polyprotein. J Virol. 1993 Jul;67(7):4017–4026. doi: 10.1128/jvi.67.7.4017-4026.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tsukiyama-Kohara K., Kohara M., Yamaguchi K., Maki N., Toyoshima A., Miki K., Tanaka S., Hattori N., Nomoto A. A second group of hepatitis C viruses. Virus Genes. 1991 Jul;5(3):243–254. doi: 10.1007/BF00568974. [DOI] [PubMed] [Google Scholar]
- Tsukuma H., Hiyama T., Tanaka S., Nakao M., Yabuuchi T., Kitamura T., Nakanishi K., Fujimoto I., Inoue A., Yamazaki H. Risk factors for hepatocellular carcinoma among patients with chronic liver disease. N Engl J Med. 1993 Jun 24;328(25):1797–1801. doi: 10.1056/NEJM199306243282501. [DOI] [PubMed] [Google Scholar]
- Unsal H., Yakicier C., Marçais C., Kew M., Volkmann M., Zentgraf H., Isselbacher K. J., Ozturk M. Genetic heterogeneity of hepatocellular carcinoma. Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):822–826. doi: 10.1073/pnas.91.2.822. [DOI] [PMC free article] [PubMed] [Google Scholar]