Abstract
Aberrant promoter methylation of tumor suppressor genes including retinoic acid receptor-β2 (RAR-β2) is frequently detected in hepatitis C virus (HCV)-associated hepatocellular carcinoma; however, the mechanism and its significance are relatively unknown. Here, we showed that HCV Core induced promoter hypermethylation of RAR-β2 to inhibit its expression via up-regulation of DNA methyltransferases 1 and 3b. Under the condition, all-trans retinoic acid (ATRA) failed to activate p16 expression and thus could not inactivate the Rb-E2F pathway. Accordingly, Core-expressing cells exhibited resistance to ATRA-induced growth inhibition. Taken together, HCV Core antagonizes ATRA, a natural anti-cancer compound, to stimulate cell growth via epigenetic down-regulation of RAR-β2.
Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Carcinoma, Hepatocellular
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cyclin-Dependent Kinase Inhibitor p16
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DNA Methylation*
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Down-Regulation
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Gene Expression Regulation, Neoplastic
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Hep G2 Cells
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Hepacivirus
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Hepatitis C Antigens / metabolism*
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Humans
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Liver Neoplasms
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Methyltransferases / biosynthesis
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Neoplasm Proteins / biosynthesis
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Promoter Regions, Genetic
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RNA Interference
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RNA, Small Interfering
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Receptors, Retinoic Acid / genetics
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Receptors, Retinoic Acid / metabolism*
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Tretinoin / pharmacology*
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Viral Core Proteins / metabolism*
Substances
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CDKN2A protein, human
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Cyclin-Dependent Kinase Inhibitor p16
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Hepatitis C Antigens
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Neoplasm Proteins
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RNA, Small Interfering
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Receptors, Retinoic Acid
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Viral Core Proteins
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nucleocapsid protein, Hepatitis C virus
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retinoic acid receptor beta
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Tretinoin
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Methyltransferases