title: Hepatitis B virus X protein upregulates oncogene Rab18 to result in the dysregulation of lipogenesis and proliferation of hepatoma cells.
abstract: Hepatitis B virus X protein (HBx) contributes to the development of hepatocellular carcinoma (HCC) through inducing dysregulation of lipogenesis. However, the mechanism by which HBx induces the abnormal lipogenesis is not well known. In this study, we report that the oncogene Rab18, a member of Ras family, enhances the HBx-induced hepatocarcinogenesis through inducing dysregulation of lipogenesis and proliferation. Our data showed that the expression levels of Rab18 were positively associated with those of HBx in clinical HCC tissues. HBx was able to upregulate the expression of Rab18 in p21-HBx transgenic mice and hepatoma cell lines. Next, we identified the mechanism by which HBx upregulated Rab18. The results demonstrated that cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) were able to stimulate Rab18 promoter through activating transcription factor activator protein 1 (AP-1) and cyclic adenosine 3',5'-monophosphate response element-binding (CREB). In addition, we identified another pathway that HBx activated Rab18. We found that miR-429 was able to directly target the 3' untranslated region of Rab18, suggesting that Rab18 is one of the target genes of miR-429. Then, we found that HBx was able to downregulate miR-429 in hepatoma cells. The oil red O staining showed that HBx resulted in the dysregulation of lipogenesis through Rab18. Moreover, Rab18 contributed to the HBx-enhanced proliferation of hepatoma cells in vitro and in vivo. HBx enhances hepatocarcinogenesis through leading to the dysregulation of lipogenesis and proliferation of hepatoma cells, involving two pathways such as HBx/COX-2/5-LOX/AP-1/CREB/Rab18 and HBx/miR-429/Rab18.
authors.affiliation: Department of Cancer Research, Key Laboratory of Molecular Microbiology and Technology of Ministry of Education, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Xiaona
authors.initials: X
authors.lastname: You
authors.forename: Fabao
authors.initials: F
authors.lastname: Liu
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Li
authors.forename: Lihong
authors.initials: L
authors.lastname: Ye
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001665:Binding Sites; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D015967:Gene Expression Regulation, Viral; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006515:Hepatitis B virus; D006801:Humans; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D054334:Viral Regulatory and Accessory Proteins; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; C546363:MIRN429 microRNA, human; D035683:MicroRNAs; C484168:RAB18 protein, human; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D020691:rab GTP-Binding Proteins