NS3 protein of hepatitis C virus regulates cyclooxygenase-2 expression through multiple signaling pathways.
Hepatitis C virus (HCV) causes chronic hepatitis, which often results in the development of liver cirrhosis and hepatocellular carcinoma (HCC) worldwide. In this study, we demonstrated that the non-structural protein NS3 of HCV enhances cyclooxygenase-2 (COX-2) gene promoter activity, COX-2 mRNA expression, COX-2 protein production, and prostaglandin E2 (PGE2) release in HepG2 cells in a concentration-dependent fashion. We also showed that transcription factor NF-kappaB is required for the activation of COX-2 regulated by NS3. In addition, multiple signaling pathways are involved cooperatively in the expression of COX-2 activated by the viral protein in a calcium-independent manner, which requires signaling components including JNK, ERK, and PKD2. A thorough investigation of mechanism involved in the activation of COX-2 regulated by HCV would provide insights into our understanding the processes of liver inflammatory response and hepatocellular carcinoma development caused by the viral infection and also into the development of novel therapeutics against HCV infection.
Lu
Lili
L
The State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, PR China.
Wei
Liang
L
Peng
Guiqing
G
Mu
Yongxin
Y
Wu
Kailang
K
Kang
Lei
L
Yan
Xiaohong
X
Zhu
Ying
Y
Wu
Jianguo
J
D002118:Calcium / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000821:virology; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D015232:Dinoprostone / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D016174:Hepacivirus / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000821:virology; D008156:Luciferases / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D000091283:Protein Kinase D2; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D017361:Viral Nonstructural Proteins / Q000378:metabolism* / Q000502:physiology; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D002118:Calcium; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D048031:JNK Mitogen-Activated Protein Kinases; D008156:Luciferases; D020929:Mitogen-Activated Protein Kinase Kinases; D016328:NF-kappa B; D000091283:Protein Kinase D2; D011494:Protein Kinases; D012333:RNA, Messenger; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases