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Enhanced cell survival of Hep3B cells by the hepatitis B x antigen effector, URG11, is associated with upregulation of β‐catenin
Author(s) -
Lian Zhaorui,
Liu Jie,
Li Li,
Li Xianxing,
Clayton Marcy,
Wu MengChao,
Wang HongYang,
Arbuthnot Patrick,
Kew Michael,
Fan Daiming,
Feitelson Mark A.
Publication year - 2006
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.21053
Subject(s) - downregulation and upregulation , effector , transfection , cancer research , biology , microbiology and biotechnology , cell culture , immunology , gene , biochemistry , genetics
Intrahepatic expression of hepatitis B x antigen (HBxAg) is associated with the development of hepatocellular carcinoma (HCC), perhaps through trans ‐activation of selected cellular genes. When this was examined by PowerBlot analysis, upregulated levels of β‐catenin and several known β‐catenin effectors were observed in HBxAg‐positive compared with HBxAg‐negative HepG2 cells. When HBxAg was introduced into Hep3B cells, upregulated expression of wild‐type β‐catenin was observed. This was also observed in Hep3B cells overexpressing the HBxAg upregulated gene, URG11. Upregulated expression of URG11 and β‐catenin correlated with HBxAg trans ‐activation function. Transient transfection assays with fragments of the β‐catenin promoter showed that it was activated by both HBxAg and URG11 and inhibited by URG11‐specific small inhibitory RNA. The latter also inhibited the growth of Hep3BX cells in a serum‐free medium, which correlated with depressed levels of β‐catenin. Activation of β‐catenin effector genes was observed in cells stably expressing HBxAg or overexpressing URG11 compared with control cells transfected with the pTOPFLASH reporter plasmid. Extensive costaining between HBxAg, URG11, and β‐catenin was observed in infected liver and HCC nodules, suggesting a close relationship in vivo . In conclusion , wild‐type β‐catenin is activated by HBxAg, in part, through the upregulated expression of the HBxAg effector URG11. URG11 stimulates the β‐catenin promoter and hepatocellular growth and survival. These observations also suggest that URG11 may be a regulatory element in the β‐catenin signaling pathway and may be a target for chemoprevention of HCC. (H EPATOLOGY 2006;43:415–424.)