Hepatitis C virus induces a mutator phenotype: enhanced mutations of immunoglobulin and protooncogenes.
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 Ig 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 Ig 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.
Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, 2011 Zonal Avenue, Los Angeles, CA 90033, USA.
Keigo
K
Machida
Kevin T-N
KT
Cheng
Vicky M-H
VM
Sung
Shigetaka
S
Shimodaira
Karen L
KL
Lindsay
Alexandra M
AM
Levine
Ming-Yang
MY
Lai
Michael M C
MM
Lai
D001402:B-Lymphocytes / Q000378:metabolism; D003564:Cytidine Deaminase / Q000378:metabolism; D004249:DNA Damage; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D016174:Hepacivirus / Q000378:metabolism*; D006526:Hepatitis C / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics*; D009154:Mutation; D011519:Proto-Oncogenes; D034741:RNA, Small Interfering
D007136:Immunoglobulins; D034741:RNA, Small Interfering; D004259:DNA-Directed DNA Polymerase; D003564:Cytidine Deaminase