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Article: C-terminal truncated HBx protein activates caveolin-1/LRP6/β-catenin/FRMD5 axis in promoting hepatocarcinogenesis

TitleC-terminal truncated HBx protein activates caveolin-1/LRP6/β-catenin/FRMD5 axis in promoting hepatocarcinogenesis
Authors
KeywordsMetastasis
MicroRNA
Therapeutics
Biomarker
Protein stability
Issue Date2019
PublisherElsevier Ireland Ltd. The Journal's web site is located at http://www.elsevier.com/locate/canlet
Citation
Cancer Letters, 2019, v. 444, p. 60-69 How to Cite?
AbstractHepatitis B virus X protein mutants, particularly truncated at C-terminal (HBxΔC), generated during random viral integration, are frequently detected in hepatocellular carcinoma (HCC) and exert a more potent oncogenic effect than full-length form (FL). Here, we showed that caveolin-1 (Cav1), a robust metastasis promoter, is transcriptionally upregulated by HBxΔC but not by FL HBx. Promoting effect of HBxΔC in HCC cell aggressiveness is abolished when Cav1 is suppressed. Expression profiling identified FERM domain containing 5 (FRMD5) protein as a downstream target of Cav1. In accordance with the regulation of Cav1, HBxΔC upregulates FRMD5. Knockdown of FRMD5 in HBxΔC cells recapitulated the functional effect of Cav1 knockdown in HBxΔC cells. The regulation of FRMD5 by HBxΔC-induced Cav1 is mediated by the protein stablilization of LRP6 leading to the activation of β-catenin. Expression of a constitutively active β-catenin in Cav1 knockdown cells rescued FRMD5 expression and HCC tumorigenesis and metastasis. Clinical relevance of HBxΔC/Cav1/LRP6/FRMD5 pathway is demonstrated by the significant correlation of Cav1, LRP6 and FRMD5 expressions in HCC. The findings of this study uncover a novel HBxΔC-regulated molecular pathway which has profound implications in HCC therapeutics.
Persistent Identifierhttp://hdl.handle.net/10722/272153
ISSN
2017 Impact Factor: 6.491
2015 SCImago Journal Rankings: 2.331
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorMao, X-
dc.contributor.authorTey, SK-
dc.contributor.authorKo, FCF-
dc.contributor.authorKwong, EML-
dc.contributor.authorGao, Y-
dc.contributor.authorNg, IOL-
dc.contributor.authorCheung, ST-
dc.contributor.authorGuan, XY-
dc.contributor.authorYam, JWP-
dc.date.accessioned2019-07-20T10:36:42Z-
dc.date.available2019-07-20T10:36:42Z-
dc.date.issued2019-
dc.identifier.citationCancer Letters, 2019, v. 444, p. 60-69-
dc.identifier.issn0304-3835-
dc.identifier.urihttp://hdl.handle.net/10722/272153-
dc.description.abstractHepatitis B virus X protein mutants, particularly truncated at C-terminal (HBxΔC), generated during random viral integration, are frequently detected in hepatocellular carcinoma (HCC) and exert a more potent oncogenic effect than full-length form (FL). Here, we showed that caveolin-1 (Cav1), a robust metastasis promoter, is transcriptionally upregulated by HBxΔC but not by FL HBx. Promoting effect of HBxΔC in HCC cell aggressiveness is abolished when Cav1 is suppressed. Expression profiling identified FERM domain containing 5 (FRMD5) protein as a downstream target of Cav1. In accordance with the regulation of Cav1, HBxΔC upregulates FRMD5. Knockdown of FRMD5 in HBxΔC cells recapitulated the functional effect of Cav1 knockdown in HBxΔC cells. The regulation of FRMD5 by HBxΔC-induced Cav1 is mediated by the protein stablilization of LRP6 leading to the activation of β-catenin. Expression of a constitutively active β-catenin in Cav1 knockdown cells rescued FRMD5 expression and HCC tumorigenesis and metastasis. Clinical relevance of HBxΔC/Cav1/LRP6/FRMD5 pathway is demonstrated by the significant correlation of Cav1, LRP6 and FRMD5 expressions in HCC. The findings of this study uncover a novel HBxΔC-regulated molecular pathway which has profound implications in HCC therapeutics.-
dc.languageeng-
dc.publisherElsevier Ireland Ltd. The Journal's web site is located at http://www.elsevier.com/locate/canlet-
dc.relation.ispartofCancer Letters-
dc.subjectMetastasis-
dc.subjectMicroRNA-
dc.subjectTherapeutics-
dc.subjectBiomarker-
dc.subjectProtein stability-
dc.titleC-terminal truncated HBx protein activates caveolin-1/LRP6/β-catenin/FRMD5 axis in promoting hepatocarcinogenesis-
dc.typeArticle-
dc.identifier.emailMao, X: susanmao@hku.hk-
dc.identifier.emailTey, SK: szekeong@hku.hk-
dc.identifier.emailKo, FCF: bokcf@hku.hk-
dc.identifier.emailKwong, EML: ernest18@hku.hk-
dc.identifier.emailNg, IOL: iolng@hku.hk-
dc.identifier.emailGuan, XY: xyguan@hku.hk-
dc.identifier.emailYam, JWP: judyyam@pathology.hku.hk-
dc.identifier.authorityNg, IOL=rp00335-
dc.identifier.authorityGuan, XY=rp00454-
dc.identifier.authorityYam, JWP=rp00468-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.canlet.2018.12.003-
dc.identifier.pmid30583072-
dc.identifier.scopuseid_2-s2.0-85058962084-
dc.identifier.hkuros298461-
dc.identifier.volume444-
dc.identifier.spage60-
dc.identifier.epage69-
dc.identifier.isiWOS:000457505400006-
dc.publisher.placeIreland-

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