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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
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TitleCell cycle-related kinase is a direct androgen receptor-regulated gene that drives β-catenin/T cell factor-dependent hepatocarcinogenesis
 
AuthorsFeng, H3
Cheng, ASL3
Tsang, DP3
Li, MS3
Go, MY3
Cheung, YS3
Zhao, GJ2
Ng, SS1
Lin, MC3
Yu, J3
Lai, PB3
To, KF3
Sung, JJY3
 
Issue Date2011
 
PublisherAmerican Society for Clinical Investigation. The Journal's web site is located at http://www.jci.org
 
CitationJournal Of Clinical Investigation, 2011, v. 121 n. 8, p. 3159-3175 [How to Cite?]
DOI: http://dx.doi.org/10.1172/JCI45967
 
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.
 
ISSN0021-9738
2013 Impact Factor: 13.765
2013 SCImago Journal Rankings: 9.511
 
DOIhttp://dx.doi.org/10.1172/JCI45967
 
PubMed Central IDPMC3148736
 
ISI Accession Number IDWOS:000293495500026
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.

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorFeng, H
 
dc.contributor.authorCheng, ASL
 
dc.contributor.authorTsang, DP
 
dc.contributor.authorLi, MS
 
dc.contributor.authorGo, MY
 
dc.contributor.authorCheung, YS
 
dc.contributor.authorZhao, GJ
 
dc.contributor.authorNg, SS
 
dc.contributor.authorLin, MC
 
dc.contributor.authorYu, J
 
dc.contributor.authorLai, PB
 
dc.contributor.authorTo, KF
 
dc.contributor.authorSung, JJY
 
dc.date.accessioned2011-09-23T06:22:12Z
 
dc.date.available2011-09-23T06:22:12Z
 
dc.date.issued2011
 
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.
 
dc.description.naturepublished_or_final_version
 
dc.identifier.citationJournal Of Clinical Investigation, 2011, v. 121 n. 8, p. 3159-3175 [How to Cite?]
DOI: http://dx.doi.org/10.1172/JCI45967
 
dc.identifier.doihttp://dx.doi.org/10.1172/JCI45967
 
dc.identifier.epage3175
 
dc.identifier.hkuros196583
 
dc.identifier.isiWOS:000293495500026
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.

 
dc.identifier.issn0021-9738
2013 Impact Factor: 13.765
2013 SCImago Journal Rankings: 9.511
 
dc.identifier.issue8
 
dc.identifier.pmcidPMC3148736
 
dc.identifier.pmid21747169
 
dc.identifier.scopuseid_2-s2.0-79961013561
 
dc.identifier.spage3159
 
dc.identifier.urihttp://hdl.handle.net/10722/140940
 
dc.identifier.volume121
 
dc.languageeng
 
dc.publisherAmerican Society for Clinical Investigation. The Journal's web site is located at http://www.jci.org
 
dc.publisher.placeUnited States
 
dc.relation.ispartofJournal of Clinical Investigation
 
dc.relation.referencesReferences in Scopus
 
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 hepatocarcinogenesis
 
dc.typeArticle
 
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<contributor.author>Lai, PB</contributor.author>
<contributor.author>To, KF</contributor.author>
<contributor.author>Sung, JJY</contributor.author>
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<description.abstract>Hepatocellular 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 &#946;-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 &#946;-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 &#946;-catenin or TCF. In primary human HCC tissue samples, AR, CCRK, and &#946;-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 &#946;-catenin/TCF signaling.</description.abstract>
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Author Affiliations
  1. The University of Hong Kong
  2. Inner Mongolia University China
  3. Chinese University of Hong Kong