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首页> 外文期刊>The journal of clinical investigation >Cell cycle–related kinase is a direct androgen receptor–regulated gene that drives β-catenin/T cell factor–dependent hepatocarcinogenesis
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Cell cycle–related kinase is a direct androgen receptor–regulated gene that drives β-catenin/T cell factor–dependent hepatocarcinogenesis

机译：细胞周期相关激酶是直接受雄激素受体调节的基因，可驱动依赖β-catenin/ T细胞因子的肝癌发生

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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.
机译：肝细胞癌（HCC）是全球第五大最常见的癌症。男性比女性更普遍。与此相关的是，最近的遗传研究表明，雄激素受体（AR）在肝癌发生中具有因果作用，但潜在的分子机制仍不清楚。在这里，我们使用了全基因组的位置和功能分析来确定AR信号的关键介体-细胞周期相关激酶（CCRK）-通过依赖于β-catenin和T细胞因子（TCF）的信号通路驱动肝癌的发生。配体结合的AR通过与人HCC细胞系中CCRK启动子的雄激素响应元件直接结合来激活CCRK转录和蛋白质表达。体外分析表明，CCRK在人类细胞系中对于AR诱导的细胞周期进程，肝细胞增殖和恶性转化至关重要。 CCRK在永生化人类肝细胞中的异位表达激活了β-catenin/ TCF信号，以刺激细胞周期进程并诱导肿瘤形成，这在异种移植和原位移植模型中均显示。相反，敲除CCRK会降低HCC细胞的生长，这可以通过组成型活性β-catenin或TCF来挽救。在原发性人类HCC组织样品中，AR，CCRK和β-catenin在肿瘤细胞中一致地过度表达。此外，CCRK的过表达与肿瘤的分期和患者的总体存活率低有关。我们的结果揭示了直接的AR转录靶CCRK，它通过上调β-catenin/ TCF信号传导来促进肝癌的发生。

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