Epigenetic analysis of hepatocellular carcinoma development : involvement of HBV-modulated DNA methylation.
Date of Issue2010
School of Chemical and Biomedical Engineering
Hepatocellular carcinoma (HCC) is one of the most aggressive human malignancies. Epidemiological studies have shown that HCC is closely associated with chronic hepatitis B virus (HBV). However, the underlying mechanisms of the HBV-associated HCC development remain unclear. DNA methylation, one of the mechanisms in epigenetics, affects gene expression at the transcriptional level. Evidence has revealed the association between HCC and HBV-mediated DNA methylation. Within the four proteins encoded by HBV genome, the HBV X protein (HBx) has been found to epigenetically inhibit some tumor suppressor genes (TSGs), which may lead to development of HCC. To investigate comprehensively the role of HBV/HBx in DNA methylation, a protein profile affected by HBV in HBV-producing HepG2.2.15 cells compared with HepG2, was analyzed by our iTRAQ-coupled 2-D LC/MS-MS analysis. Fifteen proteins including S100A6 and ANXA2 were identified. A role of these proteins as target of HBV-mediated DNA methylation was supported by validation assays, including their re-activation in cells treated with 5-Aza-dC (a DNA methyltransferase inhibitor). DNA methylation analysis suggested that, the proteins were down-regulated by HBV via DNA hypermethylation.