Carboxyl-Terminal Truncated HBx Regulates a Distinct MicroRNA Transcription Program in Hepatocellular Carcinoma Development 英文参考文献.docVIP

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Carboxyl-Terminal Truncated HBx Regulates a Distinct MicroRNA Transcription Program in Hepatocellular Carcinoma Development 英文参考文献.doc

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Carboxyl-Terminal Truncated HBx Regulates a Distinct MicroRNA Transcription Program in Hepatocellular Carcinoma Development 英文参考文献

Carboxyl-TerminalTruncatedHBxRegulatesaDistinct MicroRNATranscriptionPrograminHepatocellular CarcinomaDevelopment Wing-KitYip1,2,AlfredSze-LokCheng1*,RanxuZhu1,2,RaymondWai-MingLung3,DaisyPui-Fong Tsang1,2,SukiShuk-KeiLau1,YangchaoChen2¤a,JonathanGabrielSung1,2,PaulBo-SanLai1,4 ,Enders Kai-OnNg1¤b,JunYu1,2,NathalieWong3,Ka-FaiTo1,3,VincentWai-SunWong1,2,JosephJao-YiuSung1,2 HenryLik-YuenChan1,2 , 1InstituteofDigestiveDisease,TheChineseUniversityofHongKong,HongKongSAR,China,2DepartmentofMedicineandTherapeutics,TheChineseUniversityof HongKong,HongKongSAR,China,3DepartmentofAnatomicalandCellularPathology,TheChineseUniversityofHongKong,HongKongSAR,China,4Departmentof Surgery,TheChineseUniversityofHongKong,HongKongSAR,China Abstract Background:ThebiologicalpathwaysandfunctionalpropertiesbywhichmisexpressedmicroRNAs(miRNAs)contributeto liver carcinogenesis have been intensively investigated. However, little is known about the upstream mechanisms that deregulatemiRNAexpressionsinthisprocess.Inhepatocellularcarcinoma(HCC),hepatitisBvirus(HBV)Xprotein(HBx),a transcriptional trans-activator, isfrequently expressed intruncated formwithoutcarboxyl-terminus but itsrole inmiRNA expressionandHCCdevelopmentisunclear. Methods:Humannon-tumorigenichepatocyteswereinfectedwithlentivirus-expressingfull-lengthandcarboxyl-terminal truncated HBx (Ct-HBx) for cell growth assay and miRNA profiling. Chromatin immunoprecipitation microarray was performed to identify the miRNA promoters directly associated with HBx. Direct transcriptional control was verified by luciferase reporter assay. The differential miRNA expressions were further validated in a cohort of HBV-associated HCC tissuesusingreal-timePCR. Results:HepatocytesexpressingCt-HBxgrewsignificantlyfasterthanthefull-lengthHBxcounterparts.Ct-HBxdecreased whilefull-lengthHBxincreasedtheexpressionofasetofmiRNAswithgrowth-suppressivefunctions.Interestingly,Ct-HBx bound to and inhibited the transcriptional activity of some of these miRNA pro