title: HBx induces the proliferation of hepatocellular carcinoma cells via AP1 over-expressed as a result of ER stress.
abstract: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and chronic hepatitis B virus (HBV) infection is the most common risk factor for HCC. The HBV proteins can induce oncogenic or synergy effects with a hyperproliferative response on transformation into HCC. CREBH (cAMP-responsive, element-binding protein H), activated by stress in the endoplasmic reticulum (ER), is an ER-resident transmembrane bZIP (basic leucine zipper) transcription factor that is specifically expressed in the liver. In the present study, we address the role played by CREBH activated by ER stress in HBV-induced hepatic cell proliferation. We confirmed CREBH activation by ER stress and showed that it occurred as a result of/via hepatitis B virus X (HBx)-induced ER stress. CREBH activated by HBx increased the expression of AP-1 target genes through c-Jun induction. Under pathological conditions such as liver damage or liver regeneration, activated CREBH may have an important role to play in hepatic inflammation and cell proliferation, as an insulin receptor with dual functions under these conditions. We showed that CREBH activated by HBx interacted with HBx protein, leading to a synergistic effect on the expression of AP-1 target genes and the proliferation of HCC cells and mouse primary hepatocytes. In conclusion, in HBV-infected hepatic cells or patients with chronic HBV, CREBH may induce proliferation of hepatic cells in co-operation with HBx, resulting in HCC.
authors.affiliation: *Department of Molecular Biology, Pusan National University, Busan, Republic of Korea.
authors.forename: Hyun Kook
authors.initials: HK
authors.lastname: Cho
authors.affiliation: *Department of Molecular Biology, Pusan National University, Busan, Republic of Korea.
authors.forename: So Young
authors.initials: SY
authors.lastname: Kim
authors.affiliation: †Experimental Medicine Research Division, Department of Medical Research (Lower Myanmar), Yangon, Myanmar.
authors.forename: Yi Yi
authors.initials: YY
authors.lastname: Kyaw
authors.affiliation: †Experimental Medicine Research Division, Department of Medical Research (Lower Myanmar), Yangon, Myanmar.
authors.forename: Aye Aye
authors.initials: AA
authors.lastname: Win
authors.affiliation: ‡Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
authors.forename: Seung-Hoi
authors.initials: SH
authors.lastname: Koo
authors.affiliation: §Department of Experimental Medicine, Pusan National University Hospital, Busan, Republic of Korea.
authors.forename: Hyeong-Hoe
authors.initials: HH
authors.lastname: Kim
authors.affiliation: *Department of Molecular Biology, Pusan National University, Busan, Republic of Korea.
authors.forename: Jaehun
authors.initials: J
authors.lastname: Cheong
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics* / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism / Q000821:virology; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000235:genetics* / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D061251:Primary Cell Culture; D011485:Protein Binding; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics* / Q000378:metabolism; D054334:Viral Regulatory and Accessory Proteins
chemical_list: C533813:CREB3L3 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D008156:Luciferases