title: HBx protein promotes oval cell proliferation by up-regulation of cyclin D1 via activation of the MEK/ERK and PI3K/Akt pathways.
abstract: Growing evidence has shown that hepatic oval cells, also named liver progenitor cells, play an important role in the process of liver regeneration in various liver diseases. Oval cell proliferation has been reported in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) and chronic liver disease. Studies have found expression of HBV surface and core antigens in oval cells in the livers of patients with HCC, suggesting that HBV infection of oval cells could be a mechanism of human hepatocarcinogenesis. In addition, there is evidence of multiplication of HBV in oval cell culture. However, little research has been performed to explore the role of HBV-encoded proteins in the proliferation of hepatic oval cells. Previously, we successfully transfected the HBV x (HBx) gene, one of the four genes in the HBV genome, into a rat LE/6 oval cell line. In this study, we tested whether or not the transfected HBx gene could affect oval cell proliferation in vitro. Our results show that overexpression of HBx promotes the proliferation of oval cells and increases cyclin D1 expression, assessed at both the mRNA and protein levels. We also found that HBx activated the PI-3K/Akt and MEK/ERK1/2 pathways in HBx-transfected oval cells. Furthermore, the HBx-induced increases in cyclin D1 expression and oval cell proliferation were completely abolished by treatment with either MEK inhibitor PD184352 or PI-3K inhibitor LY294002. These results demonstrated that HBx has the ability to promote oval cell proliferation in vitro, and its stimulatory effects on cell proliferation and expression of cyclin D1 depend on the activation of the MEK/ERK and PI3K/Akt signaling pathways in cultured oval cells.
authors.affiliation: Department of Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China. gdh00909@sina.com.
authors.forename: Heng-Yi
authors.initials: HY
authors.lastname: Wang
authors.affiliation: Department of General Surgery, Liyuan Hospital, Tongji Medical College, Huazhong Science and Technology University, Wuhan 430077, China. jixufendou2013@gmail.com.
authors.forename: Sheng-Li
authors.initials: SL
authors.lastname: Yang
authors.affiliation: Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong Science and Technology University, Wuhan 430030, China. lianghuifang1997@126.com.
authors.forename: Hui-Fang
authors.initials: HF
authors.lastname: Liang
authors.affiliation: Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong Science and Technology University, Wuhan 430030, China. lichvip@126.com.
authors.forename: Chang-Hai
authors.initials: CH
authors.lastname: Li
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D001549:Benzamides; D002867:Chromones; D019938:Cyclin D1; D004791:Enzyme Inhibitors; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; C057628:hepatitis B virus X protein; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one