Carcinogenesis Advance Access originally published online on April 2, 2007
Carcinogenesis 2007 28(7):1552-1560; doi:10.1093/carcin/bgm075
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Published by Oxford University Press 2007.
Induction of a unique gene expression profile in primary human hepatocytes by hepatitis C virus core, NS3 and NS5A proteins
1 Laboratory of Human Carcinogenesis
2 Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
3 Department of Radiation Oncology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298-0058, USA
* Present address: Center for Human Genomics, Wake Forest University School of Medicine, Medical Center Blvd. Winston-Salem, NC 27157, USA
4 To whom correspondence should be addressed. Tel: +301 496 2099; Email: xw3u{at}nih.gov; Fax: 301 496 0497
Hepatocellular carcinoma (HCC) is a fatal disease and hepatitis B and C viruses (HBV and HCV) are considered as major causative factors for the development of HCC. We have conducted gene expression profiling studies to search for potential target genes responsible for HCV-mediated HCC. Adenoviruses encoding core (HCV structural protein), NS3 and NS5A [HCV non-structural (NS) proteins] were generated and infected individually or together in freshly isolated primary human hepatocytes. An adenovirus harboring the oncogenic HBV protein, HBx, was included for comparison. A microarray platform of over 22 000 human oligos was analyzed to seek out significant differentially expressed genes among these viral proteins. We also compared these gene expression profiles with those obtained from HCV-infected liver samples from chronic liver disease (CLD) patients and HCV-related HCC. We found that HCV-related proteins largely induce unique genes when compared with HBx. In particular, interferon-inducible gene 27 (IFI27) was highly expressed in HCV or core-infected hepatocytes and HCV-related CLD or HCC, but was not significantly expressed in HBx-infected hepatocytes or HBV-related CLD or HCC, indicating that IFI27 may play a role in HCV-mediated HCC. In conclusion, our results suggest that HBV and HCV promote HCC development mainly through different mechanisms.
Abbreviations: ß-gal, ß-galactosidase; CLD, chronic liver disease; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; IFI27, interferon-inducible gene 27; MOI, multiplicity of infection; NS, non-structural; qRT–PCR, quantitative reverse transcription–polymerase chain reaction
Received February 1, 2007; revised March 26, 2007; accepted March 26, 2007.