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

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TitleCarboxyl-terminal truncated HBx regulates a distinct microRNA transcription program in Hepatocellular carcinoma development
AuthorsYip, WK2
Cheng, ASL2
Zhu, R2
Lung, RWM2
Tsang, DPF2
Lau, SSK2
Chen, Y2
Sung, JG2
Lai, PBS2
Ng, EKO1 2
Yu, J2
Wong, N2
To, KF2
Wong, VWS2
Sung, JJY2
Chan, HLY2
Issue Date2011
PublisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.action
CitationPlos One, 2011, v. 6 n. 8 [How to Cite?]
DOI: http://dx.doi.org/10.1371/journal.pone.0022888
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.
ISSN1932-6203
2011 Impact Factor: 4.092
2011 SCImago Journal Rankings: 0.519
DOIhttp://dx.doi.org/10.1371/journal.pone.0022888
ISI Accession Number IDWOS:000293561200034
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.

PubMed Central IDPMC3150371
ReferencesReferences in Scopus
DC Field
Value
dc.contributor.authorYip, WK
dc.contributor.authorCheng, ASL
dc.contributor.authorZhu, R
dc.contributor.authorLung, RWM
dc.contributor.authorTsang, DPF
dc.contributor.authorLau, SSK
dc.contributor.authorChen, Y
dc.contributor.authorSung, JG
dc.contributor.authorLai, PBS
dc.contributor.authorNg, EKO
dc.contributor.authorYu, J
dc.contributor.authorWong, N
dc.contributor.authorTo, KF
dc.contributor.authorWong, VWS
dc.contributor.authorSung, JJY
dc.contributor.authorChan, HLY
dc.date.accessioned2012-02-03T06:15:12Z
dc.date.available2012-02-03T06:15:12Z
dc.date.issued2011
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.
dc.description.naturepublished_or_final_version
dc.identifier.citationPlos One, 2011, v. 6 n. 8 [How to Cite?]
DOI: http://dx.doi.org/10.1371/journal.pone.0022888
dc.identifier.doihttp://dx.doi.org/10.1371/journal.pone.0022888
dc.identifier.epagee22888
dc.identifier.hkuros198393
dc.identifier.isiWOS:000293561200034
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.

dc.identifier.issn1932-6203
2011 Impact Factor: 4.092
2011 SCImago Journal Rankings: 0.519
dc.identifier.issue8
dc.identifier.pmcidPMC3150371
dc.identifier.pmid21829663
dc.identifier.scopuseid_2-s2.0-79961136142
dc.identifier.spagee22888
dc.identifier.urihttp://hdl.handle.net/10722/144600
dc.identifier.volume6
dc.languageeng
dc.publisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.action
dc.publisher.placeUnited States
dc.relation.ispartofPLoS ONE
dc.relation.referencesReferences in Scopus
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 development
dc.typeArticle
Author Affiliations
  1. The University of Hong Kong
  2. Chinese University of Hong Kong