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Article: Cell cycle-related kinase is a direct androgen receptor-regulated gene that drives β-catenin/T cell factor-dependent hepatocarcinogenesis

TitleCell cycle-related kinase is a direct androgen receptor-regulated gene that drives β-catenin/T cell factor-dependent hepatocarcinogenesis
Authors
Issue Date2011
PublisherAmerican Society for Clinical Investigation. The Journal's web site is located at http://www.jci.org
Citation
Journal Of Clinical Investigation, 2011, v. 121 n. 8, p. 3159-3175 How to Cite?
AbstractHepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. It is more prevalent in men than women. Related to this, recent genetic studies have revealed a causal role for androgen receptor (AR) in hepatocarcinogenesis, but the underlying molecular mechanism remains unclear. Here, we used genome-wide location and functional analyses to identify a critical mediator of AR signaling - cell cycle-related kinase (CCRK) - that drives hepatocarcinogenesis via a signaling pathway dependent on β-catenin and T cell factor (TCF). Ligand-bound AR activated CCRK transcription and protein expression via direct binding to the androgen- responsive element of the CCRK promoter in human HCC cell lines. In vitro analyses showed that CCRK was critical in human cell lines for AR-induced cell cycle progression, hepatocellular proliferation, and malignant transformation. Ectopic expression of CCRK in immortalized human liver cells activated β-catenin/TCF signaling to stimulate cell cycle progression and to induce tumor formation, as shown in both xenograft and orthotopic models. Conversely, knockdown of CCRK decreased HCC cell growth, and this could be rescued by constitutively active β-catenin or TCF. In primary human HCC tissue samples, AR, CCRK, and β-catenin were concordantly overexpressed in the tumor cells. Furthermore, CCRK overexpression correlated with the tumor staging and poor overall survival of patients. Our results reveal a direct AR transcriptional target, CCRK, that promotes hepatocarcinogenesis through the upregulation of β-catenin/TCF signaling.
Persistent Identifierhttp://hdl.handle.net/10722/140940
ISSN
2014 Impact Factor: 13.215
2013 SCImago Journal Rankings: 9.511
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
Research Grants Council (Hong Kong, China)CUHK462710
Chinese University of Hong Kong2041415
Funding Information:

We would like to express our gratitude to Alice Wong (University of Hong Kong, Hong Kong, China) for critical reading of the manuscript and the provision of the dp beta-catenin, dpTCF, and dnTCF vectors for this study. We thank N. Maitland (University of York) for provision of the AR-expressing vector. We also thank Joanna Tong and Wei Kang for their excellent technical support. This work was supported by the General Research Fund (Ref. No. CUHK462710) from the Research Grants Council (Hong Kong, China) and the Direct Grant (Ref. No. 2041415) from the Chinese University of Hong Kong.

References

 

DC FieldValueLanguage
dc.contributor.authorFeng, Hen_HK
dc.contributor.authorCheng, ASLen_HK
dc.contributor.authorTsang, DPen_HK
dc.contributor.authorLi, MSen_HK
dc.contributor.authorGo, MYen_HK
dc.contributor.authorCheung, YSen_HK
dc.contributor.authorZhao, GJen_HK
dc.contributor.authorNg, SSen_HK
dc.contributor.authorLin, MCen_HK
dc.contributor.authorYu, Jen_HK
dc.contributor.authorLai, PBen_HK
dc.contributor.authorTo, KFen_HK
dc.contributor.authorSung, JJYen_HK
dc.date.accessioned2011-09-23T06:22:12Z-
dc.date.available2011-09-23T06:22:12Z-
dc.date.issued2011en_HK
dc.identifier.citationJournal Of Clinical Investigation, 2011, v. 121 n. 8, p. 3159-3175en_HK
dc.identifier.issn0021-9738en_HK
dc.identifier.urihttp://hdl.handle.net/10722/140940-
dc.description.abstractHepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. It is more prevalent in men than women. Related to this, recent genetic studies have revealed a causal role for androgen receptor (AR) in hepatocarcinogenesis, but the underlying molecular mechanism remains unclear. Here, we used genome-wide location and functional analyses to identify a critical mediator of AR signaling - cell cycle-related kinase (CCRK) - that drives hepatocarcinogenesis via a signaling pathway dependent on β-catenin and T cell factor (TCF). Ligand-bound AR activated CCRK transcription and protein expression via direct binding to the androgen- responsive element of the CCRK promoter in human HCC cell lines. In vitro analyses showed that CCRK was critical in human cell lines for AR-induced cell cycle progression, hepatocellular proliferation, and malignant transformation. Ectopic expression of CCRK in immortalized human liver cells activated β-catenin/TCF signaling to stimulate cell cycle progression and to induce tumor formation, as shown in both xenograft and orthotopic models. Conversely, knockdown of CCRK decreased HCC cell growth, and this could be rescued by constitutively active β-catenin or TCF. In primary human HCC tissue samples, AR, CCRK, and β-catenin were concordantly overexpressed in the tumor cells. Furthermore, CCRK overexpression correlated with the tumor staging and poor overall survival of patients. Our results reveal a direct AR transcriptional target, CCRK, that promotes hepatocarcinogenesis through the upregulation of β-catenin/TCF signaling.en_HK
dc.languageengen_US
dc.publisherAmerican Society for Clinical Investigation. The Journal's web site is located at http://www.jci.orgen_HK
dc.relation.ispartofJournal of Clinical Investigationen_HK
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subject.meshCyclin-Dependent Kinases - metabolism - physiology-
dc.subject.meshGene Expression Regulation-
dc.subject.meshLiver Neoplasms - metabolism-
dc.subject.meshReceptors, Androgen - metabolism-
dc.subject.meshTCF Transcription Factors - metabolism-
dc.titleCell cycle-related kinase is a direct androgen receptor-regulated gene that drives β-catenin/T cell factor-dependent hepatocarcinogenesisen_HK
dc.typeArticleen_HK
dc.identifier.emailNg, SS: ssmng@hku.hken_HK
dc.identifier.emailLin, MC: mcllin@hkucc.hku.hken_HK
dc.identifier.authorityNg, SS=rp00767en_HK
dc.identifier.authorityLin, MC=rp00746en_HK
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1172/JCI45967en_HK
dc.identifier.pmid21747169en_HK
dc.identifier.pmcidPMC3148736-
dc.identifier.scopuseid_2-s2.0-79961013561en_HK
dc.identifier.hkuros196583en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79961013561&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume121en_HK
dc.identifier.issue8en_HK
dc.identifier.spage3159en_HK
dc.identifier.epage3175en_HK
dc.identifier.isiWOS:000293495500026-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridFeng, H=41561340000en_HK
dc.identifier.scopusauthoridCheng, ASL=7402075036en_HK
dc.identifier.scopusauthoridTsang, DP=37094223100en_HK
dc.identifier.scopusauthoridLi, MS=41561723900en_HK
dc.identifier.scopusauthoridGo, MY=7101882939en_HK
dc.identifier.scopusauthoridCheung, YS=21933399800en_HK
dc.identifier.scopusauthoridZhao, GJ=13408962700en_HK
dc.identifier.scopusauthoridNg, SS=7403358718en_HK
dc.identifier.scopusauthoridLin, MC=7404816359en_HK
dc.identifier.scopusauthoridYu, J=35351306800en_HK
dc.identifier.scopusauthoridLai, PB=7202946421en_HK
dc.identifier.scopusauthoridTo, KF=7101911940en_HK
dc.identifier.scopusauthoridSung, JJY=35405352400en_HK

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