1. Hepatitis C virus induces a mutator phenotype: enhanced mutations of immunoglobulin and protooncogenes
- Author
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Machida, Keigo, Cheng, Kevin T.-N., Sung, Vicky M.-H., Shimodaira, Shigetaka, Lindsay, Karen L., Levine, Alexandra M., Lai, Ming-Yang, and Lai, Michael M.C.
- Subjects
Hepatitis C -- Research ,Science and technology - Abstract
Hepatitis C virus (HCV) is a nonretroviral oncogenic RNA virus, which is frequently associated with hepatocellular carcinoma (HCC) and B cell lymphoma. We demonstrated here that acute and chronic HCV infection caused a 5-to 10-fold increase in mutation frequency in lg heavy chain, BCL-6, p53, and [beta]-catenin genes of in vitro HCV-infected B cell lines and HCV-associated peripheral blood mononuclear cells, lymphomas, and HCCs. The nucleotide-substitution pattern of p53 and [beta]-catenin was different from that of lg heavy chain in HCV-infected cells, suggesting two different mechanisms of mutation. In addition, the mutated protooncogenes were amplified in HCV-associated lymphomas and HCCs, but not in lymphomas of nonviral origin or HBV-associated HCC. HCV induced error-prone DNA polymerase [zeta], polymerase [iota], and activation-induced cytidine deaminase, which together, contributed to the enhancement of mutation frequency, as demonstrated by the RNA interference experiments. These results indicate that HCV induces a mutator phenotype and may transform cells by a hit-and-run mechanism. This finding provides a mechanism of oncogenesis for an RNA virus.
- Published
- 2004