The role of cyclooxygenase-2 in chronic hepatitis B.

摘要

Background. Chronic hepatitis B virus (HBV) infection is the most important cause of liver cancer in Asia, yet the precise molecular mechanisms of HBV-associated carcinogenesis are unclear. This study endeavors to investigate the expression, regulation and possible actions of COX-2 in chronic hepatitis B (CHB).; Hypothesis. (1) COX-2 is up-regulated in CHB. (2) Up-regulation of COX-2 is due to HBV X protein (HBx). (3) Over-expression of COX-2 reduces apoptosis and increases proliferation hepatocytes.; Study 1. Immunohistochemistry and in situ hybridization revealed that COX-2 expression was confined to hepatocytes. CHB had significantly higher COX-2 expression compared with histologically normal and non-viral-infected liver controls. COX-2 expression between hepatitis B e antigen (HBeAg)-positive and -negative CHB was not significantly different, although the necro-inflammatory activity of the latter group was significantly lower. Over-expression of COX-2 in CHB was further confirmed by Western blot and RT-PCR analyses. Despite HBeAg sero-conversion, disappearance of HBV DNA in serum, normalization of liver enzyme and significant reduction of necro-inflammatory activity in patients responding to lamivudine or interferon treatment, no significant change in COX-2 expression was found.; Study 2. Immunohistochemistry showed that HBx localized in cytoplasm and nucleus of hepatocytes in CHB. Similar with COX-2, HBx expression also persisted after lamivudine or interferon treatment. Moreover, HBx and COX-2 immunostaining performed on serial sections revealed a remarkably co-localization pattern. Transfection studies showed that the fluorescent HBx fusion proteins were found in both cytoplasm and nucleus. Induction of COX-2 expression by HBx was also demonstrated.; Study 3. COX-2-specific inhibitor, NS-398, suppressed cellular proliferation and induced apoptosis of COX-2-expressing hepatocyte-derived cells in a dose-dependent manner. In contrast, COX-2 inhibition showed no significant effect on non-COX-2-expressing cells. Moreover, the results of this study suggested that NS-398-induced apoptosis might be partially mediated by the Fas/Fas ligand system.; Conclusion. The present study has demonstrated that COX-2 expression in hepatocytes is enhanced in chronic HBV infection. The elevation does not simply reflect inflammatory activity elicited by viral infection. HBx appears to co-localize with COX-2. Moreover, HBx induces COX-2 expression, which in turn promotes growth of hepatocyte-derived cells. This study thus provides a new mechanism by which HBV increases the risk of liver cancer.