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UP-REGULATION OF NFkB-DEPENDENT APG GENE BY HEPATITIS B VIRUS-ENCODED X ANTIGEN IN HEPATOCELLULAR CARCINOMA
Objective: To investigate the function of APG gene up-regulated by hepatitis B virus-encoded X antigen (HbxAg) in the occurrence of hepatocellular carcinoma.Methods and results: PCR select cDNA subtraction of HbxAg-positive HepG2 cells compared with HBxAg–negative HepG2 cells demonstrated the up-regulated expression of APG gene that encodes a 800 bases long transcript and a polypeptide consisting from 100 amino acid residues. In situ hybridization and immunostaining showed co-localized expression of APG and HbxAg in the liver tissue of hepatitis B carriers. Overexpression of APG protein stimulated the growth of HepG2 cells in serum-free medium, and partially protected cells from Fas-mediated killing, promoted cell growth in soft agar or tumor formation in nude mice. Introduction of the dominant negative inhibitor of nuclear factor kB (IkBa) into HBxAg-positive HepG2 cells decreased the levels of APG on mRNA and protein levels suggesting that its up-regulation is NFkB-dependent. Conclusion: HBxAg activation of NFkB may result in the up-regulation of APG protein that promotes growth factor-independent survival of cells and protects them against Fas-mediated killing. This factor may contribute to the persistence of infected hepatocytes during chronic infection, which is important for the later development of hepatocellular carcinoma (HCC).
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