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Article: Does the hepatitis B antigen HBx promote the appearance of liver cancer stem cells?

TitleDoes the hepatitis B antigen HBx promote the appearance of liver cancer stem cells?
Authors
Issue Date2011
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/
Citation
Cancer Research, 2011, v. 71 n. 10, p. 3701-3708 How to Cite?
AbstractHepatitis B virus (HBV) is a major etiologic agent of chronic liver disease and hepatocellular carcinoma (HCC). HBV-encoded X antigen, HBx, and pathways implicated in the self-renewal of stem cells contribute to HCC, but it is not clear whether HBx expression promotes "stemness." Thus, experiments were designed to test the hypothesis that HBx triggers malignant transformation by promoting properties that are characteristic of cancer stem cells (CSC). To test this hypothesis, HepG2 cells were stably transduced with HBx and then assayed for phenotypic and molecular characteristics of "stemness." The relationship between HBx and "stemness"-associated markers was also evaluated by immunohistochemical staining of liver and tumor tissue sections from HBV-infected patients. The results showed that Oct-4, Nanog, Klf-4, β-catenin, and epithelial cell adhesion molecule (EpCAM) were activated by HBx in vitro and in vivo. EpCAM was detected in the nuclei of human HCC cells from infected patients. HBx promotes "stemness" by activating b-catenin and epigenetic upregulation of miR-181, both of which target EpCAM. HBx expression was also associated with depressed levels of E-cadherin. Moreover, HBx stimulated cell migration, growth in soft agar, and spheroid formation. This work is the first to propose that HBV promotes "stemness" in the pathogenesis of HCC. HBx-associated upregulated expression of multiple "stemness" markers supports the hypothesis that HBx contributes to hepatocarcinogenesis, at least in part, by promoting changes in gene expression that are characteristics of CSCs. ©2011 AACR.
Persistent Identifierhttp://hdl.handle.net/10722/148639
ISSN
2015 Impact Factor: 8.556
2015 SCImago Journal Rankings: 5.372
ISI Accession Number ID
Funding AgencyGrant Number
CA104025
CA111427
Funding Information:

This work was supported by grants CA104025 and CA111427 awarded to M.A. Feitelson.

References

 

DC FieldValueLanguage
dc.contributor.authorArzumanyan, Aen_US
dc.contributor.authorFriedman, Ten_US
dc.contributor.authorNg, IOLen_US
dc.contributor.authorClayton, MMen_US
dc.contributor.authorLian, Zen_US
dc.contributor.authorFeitelson, MAen_US
dc.date.accessioned2012-05-29T06:14:17Z-
dc.date.available2012-05-29T06:14:17Z-
dc.date.issued2011en_US
dc.identifier.citationCancer Research, 2011, v. 71 n. 10, p. 3701-3708en_US
dc.identifier.issn0008-5472en_US
dc.identifier.urihttp://hdl.handle.net/10722/148639-
dc.description.abstractHepatitis B virus (HBV) is a major etiologic agent of chronic liver disease and hepatocellular carcinoma (HCC). HBV-encoded X antigen, HBx, and pathways implicated in the self-renewal of stem cells contribute to HCC, but it is not clear whether HBx expression promotes "stemness." Thus, experiments were designed to test the hypothesis that HBx triggers malignant transformation by promoting properties that are characteristic of cancer stem cells (CSC). To test this hypothesis, HepG2 cells were stably transduced with HBx and then assayed for phenotypic and molecular characteristics of "stemness." The relationship between HBx and "stemness"-associated markers was also evaluated by immunohistochemical staining of liver and tumor tissue sections from HBV-infected patients. The results showed that Oct-4, Nanog, Klf-4, β-catenin, and epithelial cell adhesion molecule (EpCAM) were activated by HBx in vitro and in vivo. EpCAM was detected in the nuclei of human HCC cells from infected patients. HBx promotes "stemness" by activating b-catenin and epigenetic upregulation of miR-181, both of which target EpCAM. HBx expression was also associated with depressed levels of E-cadherin. Moreover, HBx stimulated cell migration, growth in soft agar, and spheroid formation. This work is the first to propose that HBV promotes "stemness" in the pathogenesis of HCC. HBx-associated upregulated expression of multiple "stemness" markers supports the hypothesis that HBx contributes to hepatocarcinogenesis, at least in part, by promoting changes in gene expression that are characteristics of CSCs. ©2011 AACR.en_US
dc.languageengen_US
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/en_US
dc.relation.ispartofCancer Researchen_US
dc.subject.meshAdulten_US
dc.subject.meshAgeden_US
dc.subject.meshAntigens, Neoplasm - Metabolismen_US
dc.subject.meshCell Adhesion Molecules - Metabolismen_US
dc.subject.meshCell Line, Tumoren_US
dc.subject.meshCell Movementen_US
dc.subject.meshEpigenesis, Geneticen_US
dc.subject.meshFemaleen_US
dc.subject.meshHepatitis B Virus - Metabolismen_US
dc.subject.meshHomeodomain Proteins - Metabolismen_US
dc.subject.meshHumansen_US
dc.subject.meshKruppel-Like Transcription Factors - Metabolismen_US
dc.subject.meshLiver Neoplasms - Metabolism - Virologyen_US
dc.subject.meshMaleen_US
dc.subject.meshMiddle Ageden_US
dc.subject.meshNeoplastic Stem Cells - Cytologyen_US
dc.subject.meshOctamer Transcription Factor-3 - Metabolismen_US
dc.subject.meshTrans-Activators - Metabolismen_US
dc.subject.meshBeta Catenin - Metabolismen_US
dc.titleDoes the hepatitis B antigen HBx promote the appearance of liver cancer stem cells?en_US
dc.typeArticleen_US
dc.identifier.emailNg, IOL:iolng@hkucc.hku.hken_US
dc.identifier.authorityNg, IOL=rp00335en_US
dc.description.naturelink_to_OA_fulltexten_US
dc.identifier.doi10.1158/0008-5472.CAN-10-3951en_US
dc.identifier.pmid21464043-
dc.identifier.scopuseid_2-s2.0-79956079665en_US
dc.identifier.hkuros205482-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79956079665&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume71en_US
dc.identifier.issue10en_US
dc.identifier.spage3701en_US
dc.identifier.epage3708en_US
dc.identifier.isiWOS:000290610900027-
dc.publisher.placeUnited Statesen_US

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