ORIGINAL ARTICLE

Cell Research (2010): 563-575
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Hepatitis B virus X protein promotes liver cell proliferation via a positive cascade loop involving arachidonic acid metabolism and p-ERK1/2

Changliang Shan¹, Fuqing Xu¹, Shuai Zhang¹, Jiacong You², Xiaona You¹, Liyan Qiu¹, Jie Zheng², Lihong Ye² and Xiaodong Zhang¹

Correspondence: Xiaodong Zhang, Tel: +86-22-23506830; Fax: +86-22-23501385 E-mail: zhangxd@nankai.edu.cn; Lihong Ye, Tel: +86-22-23501385; Fax: +86-22-23501385 E-mail: yelihong@nankai.edu.cn

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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.

Cell Research (2010) 20:563–575. doi:10.1038/cr.2010.49; published online 13 April 2010

Keywords: hepatitis B virus X protein; proliferation; signal pathway; arachidonic acid metabolites; ERK