Cell cycle-related kinase mediates viral-host signalling to promote hepatitis B virus-associated hepatocarcinogenesis

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dc.contributor.authorZ Yu-
dc.contributor.authorY Q Gao-
dc.contributor.authorH Feng-
dc.contributor.authorY Y Lee-
dc.contributor.authorM S Li-
dc.contributor.authorY Tian-
dc.contributor.authorM Y Y Go-
dc.contributor.authorDae Yeul Yu-
dc.contributor.authorY S Cheung-
dc.contributor.authorP B S Lai-
dc.contributor.authorJ Yu-
dc.contributor.authorV W Wong-
dc.contributor.authorJ J Y Sung-
dc.contributor.authorH L Y Chan-
dc.contributor.authorA S L Cheng-
dc.date.accessioned2017-04-19T10:00:43Z-
dc.date.available2017-04-19T10:00:43Z-
dc.date.issued2014-
dc.identifier.issn0017-5749-
dc.identifier.uri10.1136/gutjnl-2013-305584ko
dc.identifier.urihttps://oak.kribb.re.kr/handle/201005/12388-
dc.description.abstractBACKGROUND: Androgen receptor (AR) signalling contributes to male predominance in hepatocellular carcinoma (HCC), which is more pronounced in HBV-endemic areas. Cell cycle-related kinase (CCRK) is essential for AR-induced hepatocarcinogenesis but its molecular function in HBV-associated HCC remains obscure.OBJECTIVE: To determine the molecular function of CCRK in HBV-associated HCC.DESIGN: Transcriptional regulation was assessed by chromatin immunoprecipitation, promoter mutation and luciferase reporter assays. Hepatocellular proliferation and tumourigenesis were examined by colony formation, soft agar assays and using HBV X protein (HBx) transgenic mice with low-dose exposure to diethylnitrosamine. Protein expressions were examined in clinical samples and correlated with patient survival by log-rank Mantel-Cox test.RESULTS: Overexpression of CCRK, but not its kinase-defective mutant, activated β-catenin/T cell factor signalling through phosphorylation of glycogen synthase kinase-3β (GSK-3β) at Ser9, led to upregulation of AR transcriptional activity and, subsequently, expression of HBx. The viral transactivator in turn induced CCRK expression through enhanced AR signalling, thus forming a positive regulatory loop. RNA interference silencing of CCRK, which suppressed the CCRK/GSK-3β/β-catenin/AR regulatory loop, significantly suppressed HBx-induced hepatocellular proliferation (p=0.001) and transformation (p<0.001) and remarkably reduced >80% diethylnitrosamine-mediated hepatocarcinogenesis in HBx transgenic mice. Finally, patients with HBV-associated HCC with concordant overexpression of CCRK, GSK-3β phosphorylation at Ser9, active dephosphorylated β-catenin and AR phosphorylation at Ser81 had poorer overall (HR=31.26, p<0.0001) and disease-free (HR=3.60, p<0.01) survival rates.CONCLUSIONS: Our findings highlight the critical role of CCRK in a self-reinforcing circuitry that regulates HBV-associated hepatocarcinogenesis. Further characterisation of this intricate viral-host signalling may provide new prognostic biomarkers and therapeutic targets for HCC treatment. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.-
dc.publisherBmj Publishing Group-
dc.titleCell cycle-related kinase mediates viral-host signalling to promote hepatitis B virus-associated hepatocarcinogenesis-
dc.title.alternativeCell cycle-related kinase mediates viral-host signalling to promote hepatitis B virus-associated hepatocarcinogenesis-
dc.typeArticle-
dc.citation.titleGut-
dc.citation.number11-
dc.citation.endPage1804-
dc.citation.startPage1793-
dc.citation.volume63-
dc.contributor.affiliatedAuthorDae Yeul Yu-
dc.contributor.alternativeNameYu-
dc.contributor.alternativeNameGao-
dc.contributor.alternativeNameFeng-
dc.contributor.alternativeNameLee-
dc.contributor.alternativeNameLi-
dc.contributor.alternativeNameTian-
dc.contributor.alternativeNameGo-
dc.contributor.alternativeName유대열-
dc.contributor.alternativeNameCheung-
dc.contributor.alternativeNameLai-
dc.contributor.alternativeName유준-
dc.contributor.alternativeNameWong-
dc.contributor.alternativeNameSung-
dc.contributor.alternativeNameChan-
dc.contributor.alternativeNameCheng-
dc.identifier.bibliographicCitationGut, vol. 63, no. 11, pp. 1793-1804-
dc.identifier.doi10.1136/gutjnl-2013-305584-
dc.description.journalClassY-
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