Article: Cell cycle-related kinase is a direct androgen receptor-regulated gene that drives β-catenin/T cell factor-dependent hepatocarcinogenesis
| Title | Cell cycle-related kinase is a direct androgen receptor-regulated gene that drives β-catenin/T cell factor-dependent hepatocarcinogenesis | ||||||
|---|---|---|---|---|---|---|---|
| Authors | Feng, 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 Date | 2011 | ||||||
| Publisher | American 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?] DOI: http://dx.doi.org/10.1172/JCI45967 | ||||||
| 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 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. | ||||||
| ISSN | 0021-9738 2011 Impact Factor: 13.069 2011 SCImago Journal Rankings: 2.512 | ||||||
| DOI | http://dx.doi.org/10.1172/JCI45967 | ||||||
| ISI Accession Number ID | WOS:000293495500026
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. | ||||||
| PubMed Central ID | PMC3148736 | ||||||
| References | References in Scopus |
| dc.contributor.author | Feng, H | ||||||
|---|---|---|---|---|---|---|---|
| dc.contributor.author | Cheng, ASL | ||||||
| dc.contributor.author | Tsang, DP | ||||||
| dc.contributor.author | Li, MS | ||||||
| dc.contributor.author | Go, MY | ||||||
| dc.contributor.author | Cheung, YS | ||||||
| dc.contributor.author | Zhao, GJ | ||||||
| dc.contributor.author | Ng, SS | ||||||
| dc.contributor.author | Lin, MC | ||||||
| dc.contributor.author | Yu, J | ||||||
| dc.contributor.author | Lai, PB | ||||||
| dc.contributor.author | To, KF | ||||||
| dc.contributor.author | Sung, JJY | ||||||
| dc.date.accessioned | 2011-09-23T06:22:12Z | ||||||
| dc.date.available | 2011-09-23T06:22:12Z | ||||||
| dc.date.issued | 2011 | ||||||
| dc.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 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.nature | published_or_final_version | ||||||
| dc.identifier.citation | Journal Of Clinical Investigation, 2011, v. 121 n. 8, p. 3159-3175 [How to Cite?] DOI: http://dx.doi.org/10.1172/JCI45967 | ||||||
| dc.identifier.doi | http://dx.doi.org/10.1172/JCI45967 | ||||||
| dc.identifier.epage | 3175 | ||||||
| dc.identifier.hkuros | 196583 | ||||||
| dc.identifier.isi | WOS:000293495500026
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.issn | 0021-9738 2011 Impact Factor: 13.069 2011 SCImago Journal Rankings: 2.512 | ||||||
| dc.identifier.issue | 8 | ||||||
| dc.identifier.pmcid | PMC3148736 | ||||||
| dc.identifier.pmid | 21747169 | ||||||
| dc.identifier.scopus | eid_2-s2.0-79961013561 | ||||||
| dc.identifier.spage | 3159 | ||||||
| dc.identifier.uri | http://hdl.handle.net/10722/140940 | ||||||
| dc.identifier.volume | 121 | ||||||
| dc.language | eng | ||||||
| dc.publisher | American Society for Clinical Investigation. The Journal's web site is located at http://www.jci.org | ||||||
| dc.publisher.place | United States | ||||||
| dc.relation.ispartof | Journal of Clinical Investigation | ||||||
| dc.relation.references | References in Scopus | ||||||
| dc.rights | Creative Commons: Attribution 3.0 Hong Kong License | ||||||
| dc.subject.mesh | Cyclin-Dependent Kinases - metabolism - physiology | ||||||
| dc.subject.mesh | Gene Expression Regulation | ||||||
| dc.subject.mesh | Liver Neoplasms - metabolism | ||||||
| dc.subject.mesh | Receptors, Androgen - metabolism | ||||||
| dc.subject.mesh | TCF Transcription Factors - metabolism | ||||||
| dc.title | Cell cycle-related kinase is a direct androgen receptor-regulated gene that drives β-catenin/T cell factor-dependent hepatocarcinogenesis | ||||||
| dc.type | Article |
Author Affiliations
- The University of Hong Kong
- Inner Mongolia University China
- Chinese University of Hong Kong