This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Naganuma, A. Articles by Kato, N. Search for Related Content PubMed PubMed Citation Articles by Naganuma, A. Articles by Kato, N.

Promotion of Microsatellite Instability by Hepatitis C Virus Core Protein in Human Non-neoplastic Hepatocyte Cells

Department of Molecular Biology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan

Hepatitis C virus proteins exert an effect on a variety of cellular functions, including gene expression, signal transduction, and apoptosis, and because they possess oncogenic potentials, they have also been suggested to play an important role in hepatocarcinogenesis. Although the mechanisms of hepatocarcinogenesis remain poorly understood, we hypothesized that the disease may arise because of a disturbance of the DNA repair system by hepatitis C virus proteins. To test this hypothesis, we developed a reproducible microsatellite instability assay system for mismatch-repair using human-cultured cells transducted with pCXpur retrovirus expression vector, in which the puromycin resistance gene was rendered out-of-frame by insertion of a (CA)₁₇ dinucleotide repeat tract immediately following the ATG start codon. Using several human cancer cell lines known to be replication error positive or negative, we demonstrated that this assay system was useful for monitoring the propensity for mismatch-repair in the cells. This assay system was applicable to non-neoplastic human PH5CH8 hepatocytes, which could support hepatitis C virus replication. Using PH5CH8 cells, in which hepatitis C virus proteins were stably expressed by the retrovirus-mediated gene transfer, we found that the core protein promoted microsatellite instability in PH5CH8 cells. Interestingly, such promotion by the core protein only occurred in cells having the core protein belonging to genotype 1b or 2a and did not occur in cells having the core protein belonging to genotype 1a, 2b, or 3a. This is the first report to demonstrate that the core protein may disturb the DNA repair system.

This article has been cited by other articles:

				C.-C. Wu, M.-T. Liu, Y.-T. Chang, C.-Y. Fang, S.-P. Chou, H.-W. Liao, K.-L. Kuo, S.-L. Hsu, Y.-R. Chen, P.-W. Wang, et al. Epstein-Barr Virus DNase (BGLF5) induces genomic instability in human epithelial cells Nucleic Acids Res., December 23, 2009; (2009) gkp1169v1. [Abstract] [Full Text] [PDF]

				M. F. Reynolds, E. C. Peterson-Roth, I. A. Bespalov, T. Johnston, V. M. Gurel, H. L. Menard, and A. Zhitkovich Rapid DNA Double-Strand Breaks Resulting from Processing of Cr-DNA Cross-Links by Both MutS Dimers Cancer Res., February 1, 2009; 69(3): 1071 - 1079. [Abstract] [Full Text] [PDF]

				K. Naka, K. Takemoto, K.-i. Abe, H. Dansako, M. Ikeda, K. Shimotohno, and N. Kato Interferon resistance of hepatitis C virus replicon-harbouring cells is caused by functional disruption of type I interferon receptors J. Gen. Virol., October 1, 2005; 86(10): 2787 - 2792. [Abstract] [Full Text] [PDF]

				N. Kato, T. Nakamura, H. Dansako, K. Namba, K.-i. Abe, A. Nozaki, K. Naka, M. Ikeda, and K. Shimotohno Genetic variation and dynamics of hepatitis C virus replicons in long-term cell culture J. Gen. Virol., March 1, 2005; 86(3): 645 - 656. [Abstract] [Full Text] [PDF]