title: Cell cycle-related kinase is a direct androgen receptor-regulated gene that drives β-catenin/T cell factor-dependent hepatocarcinogenesis.
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.
authors: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.
authors: Hai
authors: H
authors: Feng
authors: Alfred S L
authors: AS
authors: Cheng
authors: Daisy P
authors: DP
authors: Tsang
authors: May S
authors: MS
authors: Li
authors: Minnie Y
authors: MY
authors: Go
authors: Yue S
authors: YS
authors: Cheung
authors: Gui-jun
authors: GJ
authors: Zhao
authors: Samuel S
authors: SS
authors: Ng
authors: Marie C
authors: MC
authors: Lin
authors: Jun
authors: J
authors: Yu
authors: Paul B
authors: PB
authors: Lai
authors: Ka F
authors: KF
authors: To
authors: Joseph J Y
authors: JJ
authors: Sung
mesh_terms: D000368:Aged; D000818:Animals; D001665:Binding Sites; D002453:Cell Cycle; D018844:Cyclin-Dependent Kinases / Q000378:metabolism / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009368:Neoplasm Transplantation; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D051176:beta Catenin / Q000378:metabolism*; D000095043:Cyclin-Dependent Kinase-Activating Kinase
chemical_list: D011944:Receptors, Androgen; D051820:TCF Transcription Factors; D051176:beta Catenin; D018844:Cyclin-Dependent Kinases; D000095043:Cyclin-Dependent Kinase-Activating Kinase