Hepatitis B virus X protein promotes liver cell proliferation via a positive cascade loop involving arachidonic acid metabolism and p-ERK1/2.
Hepatitis B virus X protein (HBx) plays a crucial role in the development of hepatocellular carcinoma. Here, we sought to identify the mechanisms by which HBx mediates liver cell proliferation. We found that HBx upregulated the levels of cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX) and phosphorylated extracellular signal-regulated protein kinases 1/2 (p-ERK1/2) in liver cells. HBx-induced p-ERK1/2 was abolished by inhibition of Gi/o proteins, COX or LOX. In addition, HBx increased the amounts of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) released from cell lines derived from hepatocytes. Moreover, these released arachidonic acid metabolites were able to activate ERK1/2. Interestingly, activated ERK1/2 could upregulate the expression of COX-2 and 5-LOX in a positive feedback manner. In conclusion, HBx enhances and maintains liver cell proliferation via a positive feedback loop involving COX-2, 5-LOX, released arachidonic acid metabolites, Gi/o proteins and p-ERK1/2.
Shan
Changliang
C
Department of Cancer Research, Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, Institute For Molecular Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.
Xu
Fuqing
F
Zhang
Shuai
S
You
Jiacong
J
You
Xiaona
X
Qiu
Liyan
L
Zheng
Jie
J
Ye
Lihong
L
Zhang
Xiaodong
X
D016718:Arachidonic Acid / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000821:virology; D002460:Cell Line; D049109:Cell Proliferation; D006515:Hepatitis B virus / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology / Q000821:virology*; D006801:Humans; D008113:Liver Neoplasms / Q000821:virology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins
D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D016718:Arachidonic Acid; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3