COX-2 mediates hepatitis B virus X protein abrogation of p53-induced apoptosis.
The oncogenic hepatitis B virus X protein (HBx) and cyclooxygenase (COX)-2 are highly co-expressed in chronic hepatitis, cirrhosis and well-differentiated hepatocellular carcinoma (HCC). Although HBx is shown to activate COX-2, the functional consequences of this interaction in hepatocarcinogenesis remain unknown. Using an engineered hepatoma cell system in which the expression of wild-type p53 can be chemically modulated, we show here that COX-2 mediates HBx actions in opposing p53. Enforced expression of HBx sequestrates p53 in the cytoplasm and significantly abolishes p53-induced apoptosis. The anti-apoptotic Mcl-1 protein is suppressed by p53 but reactivated by HBx. The abrogation of apoptosis is completely reversed by specific COX-2 inhibition, suggesting that HBx blocks p53-induced apoptosis via activation of COX-2/PGE(2) pathway. We further show that COX-2 inhibition blocks HBx reactivation of Mcl-1, linking this protein to the anti-apoptotic function of COX-2. These results demonstrate that COX-2 is an important survival factor mediating the oncogenic actions of HBx. Over-expression of HBx and COX-2 may provide a selective clonal advantage for preneoplastic or neoplastic hepatocytes and contribute to the initiation and progression of HCC.
Cheng
Alfred S L
AS
Institute of Digestive Disease and Li Ka Shing Institute of Health Sciences, Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China.
Yu
Jun
J
Lai
Paul B S
PB
Chan
Henry L Y
HL
Sung
Joseph J Y
JJ
D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000821:virology*; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004318:Doxycycline / Q000494:pharmacology; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000821:virology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011230:Precancerous Conditions / Q000378:metabolism / Q000821:virology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins
D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D004318:Doxycycline