Hepatocellular carcmoma (HCC) is the third most common cause of cancer-related deaths worldwide, with a gender prevalence observed in men. Recent studies have suggested that elevated activity of the androgen axis is one major host factor underlying this disparity between genders. The androgen receptor (AR) mediates function of androgen in vital developmental and oncogenic pathways by binding to genomic androgen response elements, which influence the transcription of downstream target genes. AR is overexpressed in 60-80% of human HCCs. Genetic studies further established the pivotal role ofAR in hepatocarcinogenesis, where liver-specific knockout of AR significantly reduced tumorigenicity in carcinogen- and HBV-induced HCC mouse models. However, AR-inducedhepatocarcinogenesis is far from fully understood, in part because little is known about the identity and role of direct AR-dependent targeted genes in hepatocytes. / In this study, we used genome-wide location and functional analyses to identify a critical mediator of AR signaling, cell cycle-related kinase (CCRK), in driving beta-cateninl T-cell factor (TCF)-dependent hepatocarcinogenesis. Using chromatin immunoprecipitation followed by promoter array analysis of AR-overexpressing HCC cell lines, we found a number of cell cycle-related genes that are likely under the direct modulation of AR. Cell cycle-related kinase (CCRK), previously shown to promote glioblastoma tumorigenesis, was found to be the most significantly-bound AR target ( p<0.0001). CCRK was directly up-regulated by ligand-activated AR through promoter binding and required for AR-induced G1-S cell cycle progression because (1) CCRK overexpression attenuated cell cycle blockage by AR knockdown and (2) CCRK inhibition counteracted AR-mediated cell cycle progression. Ectopic CCRK expression induced immortalized liver cell proliferation, malignant transformation and tumor formation in immunodeficient mice, whereas CCRK inhibition decreased HCC cell growth in vitro and in vivo. These functional assays demonstrated that CCRK is a potential oncogene in HCC. Mechanistically, CCRK activated beta-catenin/TCF-dependent transcription through phosphorylation of glycogen synthase kinase-3beta and induced the expressions of beta-catenin target genes, cyclin D1 (CCND1) and epidermal growth factor receptor (EGFR). Inhibition of beta-catenin/TCF signaling attenuated CCRK-induced cell cycle progression, colony formation and tumorigenicity. Conversely, HCC cell growth inhibition by CCRK knockdown was rescued by constitutively active beta-catenin or TCF. In agreement with these findings, activation of the AR/CCRK/beta-catenin axis was frequently observed in primary HCCs. More importantly, CCRK over-expression was correlated with tumor staging and poor overall survival in a cohort ofhuman HCC tissues. / Together, our data reveal a new cascade for AR function in hepatocarcinogenesis via the activation of beta-catenin/TCF signaling. This study also reveals that CCRK is a novel focal link between two prominent signaling pathways vital for HCC growth and thus represents a new therapeutic target for HCC treatment. / Feng, Hai. / Adviser: Sung Jao Yiu. / Source: Dissertation Abstracts International, Volume: 73-04, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 161-177). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.
| Identifer | oai:union.ndltd.org:cuhk.edu.hk/oai:cuhk-dr:cuhk_344779 |
| Date | January 2011 |
| Contributors | Feng, Hai, Chinese University of Hong Kong Graduate School. Division of Medical Sciences. |
| Source Sets | The Chinese University of Hong Kong |
| Language | English, Chinese |
| Detected Language | English |
| Type | Text, theses |
| Format | electronic resource, microform, microfiche, 1 online resource (xii, 178 leaves : ill. (some col.)) |
| Rights | Use of this resource is governed by the terms and conditions of the Creative Commons “Attribution-NonCommercial-NoDerivatives 4.0 International” License (http://creativecommons.org/licenses/by-nc-nd/4.0/) |
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