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Article: Carboxyl-terminal truncated HBx regulates a distinct microRNA transcription program in Hepatocellular carcinoma development

TitleCarboxyl-terminal truncated HBx regulates a distinct microRNA transcription program in Hepatocellular carcinoma development
Authors
Issue Date2011
PublisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.action
Citation
Plos One, 2011, v. 6 n. 8 How to Cite?
AbstractBackground: The biological pathways and functional properties by which misexpressed microRNAs (miRNAs) contribute to liver carcinogenesis have been intensively investigated. However, little is known about the upstream mechanisms that deregulate miRNA expressions in this process. In hepatocellular carcinoma (HCC), hepatitis B virus (HBV) X protein (HBx), a transcriptional trans-activator, is frequently expressed in truncated form without carboxyl-terminus but its role in miRNA expression and HCC development is unclear. Methods: Human non-tumorigenic hepatocytes were infected with lentivirus-expressing full-length and carboxyl-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 tissues using real-time PCR. Results: Hepatocytes expressing Ct-HBx grew significantly faster than the full-length HBx counterparts. Ct-HBx decreased while full-length HBx increased the expression of a set of miRNAs with growth-suppressive functions. Interestingly, Ct-HBx bound to and inhibited the transcriptional activity of some of these miRNA promoters. Notably, some of the examined repressed-miRNAs (miR-26a, -29c, -146a and -190) were also significantly down-regulated in a subset of HCC tissues with carboxyl-terminal HBx truncation compared to their matching non-tumor tissues, highlighting the clinical relevance of our data. Conclusion: Our results suggest that Ct-HBx directly regulates miRNA transcription and in turn promotes hepatocellular proliferation, thus revealing a viral contribution of miRNA deregulation during hepatocarcinogenesis. © 2011 Yip et al.
Persistent Identifierhttp://hdl.handle.net/10722/144600
ISSN
2014 Impact Factor: 3.234
2014 SCImago Journal Rankings: 1.300
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
Hong Kong Government08070332
09080042
Research Grants Council09/060/GRF
462309
Collaborative Research FundCUHK04/CRF/08
Funding Information:

This work was supported by grants from the Hong Kong Government Research Fund for the Control of Infectious Diseases (08070332) to AS-LC, JJ-YS and HL-YC; (09080042) to AS-LC and JJ-YS; from the Research Grants Council General Research Fund (09/060/GRF and 462309) to AS-LC and JJ-YS; and from the Collaborative Research Fund (CUHK04/CRF/08) to AS-LC, NW and K-FT. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References

 

DC FieldValueLanguage
dc.contributor.authorYip, WKen_HK
dc.contributor.authorCheng, ASLen_HK
dc.contributor.authorZhu, Ren_HK
dc.contributor.authorLung, RWMen_HK
dc.contributor.authorTsang, DPFen_HK
dc.contributor.authorLau, SSKen_HK
dc.contributor.authorChen, Yen_HK
dc.contributor.authorSung, JGen_HK
dc.contributor.authorLai, PBSen_HK
dc.contributor.authorNg, EKOen_HK
dc.contributor.authorYu, Jen_HK
dc.contributor.authorWong, Nen_HK
dc.contributor.authorTo, KFen_HK
dc.contributor.authorWong, VWSen_HK
dc.contributor.authorSung, JJYen_HK
dc.contributor.authorChan, HLYen_HK
dc.date.accessioned2012-02-03T06:15:12Z-
dc.date.available2012-02-03T06:15:12Z-
dc.date.issued2011en_HK
dc.identifier.citationPlos One, 2011, v. 6 n. 8en_HK
dc.identifier.issn1932-6203en_HK
dc.identifier.urihttp://hdl.handle.net/10722/144600-
dc.description.abstractBackground: The biological pathways and functional properties by which misexpressed microRNAs (miRNAs) contribute to liver carcinogenesis have been intensively investigated. However, little is known about the upstream mechanisms that deregulate miRNA expressions in this process. In hepatocellular carcinoma (HCC), hepatitis B virus (HBV) X protein (HBx), a transcriptional trans-activator, is frequently expressed in truncated form without carboxyl-terminus but its role in miRNA expression and HCC development is unclear. Methods: Human non-tumorigenic hepatocytes were infected with lentivirus-expressing full-length and carboxyl-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 tissues using real-time PCR. Results: Hepatocytes expressing Ct-HBx grew significantly faster than the full-length HBx counterparts. Ct-HBx decreased while full-length HBx increased the expression of a set of miRNAs with growth-suppressive functions. Interestingly, Ct-HBx bound to and inhibited the transcriptional activity of some of these miRNA promoters. Notably, some of the examined repressed-miRNAs (miR-26a, -29c, -146a and -190) were also significantly down-regulated in a subset of HCC tissues with carboxyl-terminal HBx truncation compared to their matching non-tumor tissues, highlighting the clinical relevance of our data. Conclusion: Our results suggest that Ct-HBx directly regulates miRNA transcription and in turn promotes hepatocellular proliferation, thus revealing a viral contribution of miRNA deregulation during hepatocarcinogenesis. © 2011 Yip et al.en_HK
dc.languageengen_US
dc.publisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.actionen_HK
dc.relation.ispartofPLoS ONEen_HK
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subject.meshCarcinoma, Hepatocellular - genetics - pathology-
dc.subject.meshCell Transformation, Neoplastic-
dc.subject.meshLiver Neoplasms - genetics - pathology-
dc.subject.meshMicroRNAs - genetics-
dc.subject.meshTrans-Activators - chemistry - genetics - physiology-
dc.titleCarboxyl-terminal truncated HBx regulates a distinct microRNA transcription program in Hepatocellular carcinoma developmenten_HK
dc.typeArticleen_HK
dc.identifier.emailNg, EKO: ngko@hku.hken_HK
dc.identifier.authorityNg, EKO=rp01364en_HK
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1371/journal.pone.0022888en_HK
dc.identifier.pmid21829663-
dc.identifier.pmcidPMC3150371-
dc.identifier.scopuseid_2-s2.0-79961136142en_HK
dc.identifier.hkuros198393en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79961136142&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume6en_HK
dc.identifier.issue8en_HK
dc.identifier.spagee22888en_US
dc.identifier.epagee22888en_US
dc.identifier.isiWOS:000293561200034-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridYip, WK=35832025900en_HK
dc.identifier.scopusauthoridCheng, ASL=7402075036en_HK
dc.identifier.scopusauthoridZhu, R=49061646000en_HK
dc.identifier.scopusauthoridLung, RWM=22980272500en_HK
dc.identifier.scopusauthoridTsang, DPF=37094223100en_HK
dc.identifier.scopusauthoridLau, SSK=49061120100en_HK
dc.identifier.scopusauthoridChen, Y=24075600300en_HK
dc.identifier.scopusauthoridSung, JG=49061590200en_HK
dc.identifier.scopusauthoridLai, PBS=7202946421en_HK
dc.identifier.scopusauthoridNg, EKO=21135553700en_HK
dc.identifier.scopusauthoridYu, J=35351306800en_HK
dc.identifier.scopusauthoridWong, N=7202836653en_HK
dc.identifier.scopusauthoridTo, KF=36785812800en_HK
dc.identifier.scopusauthoridWong, VWS=7202525502en_HK
dc.identifier.scopusauthoridSung, JJY=35405352400en_HK
dc.identifier.scopusauthoridChan, HLY=25722700100en_HK

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