雄性激素受体通过CCRK促进胃癌细胞增殖的分子机制研究

Gastric cancer is one of the leading causes of cancer，and its morbidity in men is about 2 times more than women. However, the underlying mechanism has not been clarified. Androgen receptor (AR) is a member of the nuclear receptor family, is a ligand dependent transcription activating factor. Our previous studies showed AR may contribute to this difference and induce gastric cancer proliferation through cell cycle related kinase (CCRK). Immunohistochemistry data showed AR and CCRK expression in gastric cancer tissues was much higher than the adjacent normal tissues, and promoted gastric cancer cell viability in vitro. We hypothesize that AR would promote tumor proliferation in gastric cancer through regulating CCRK, which lead to the predominance of gastric cancer in male.In order to prove our hypothesis, we will conduct a series of in vitro, in vivo and clinical investigations to clarify the effect of AR and CCRK on gastric cancer tumorigenesis and development, as well as the underlying mechanism. The study will give new insight in the molecular mechanism on gastric cancer that always higher morbidities in men, and provide important scientific evidences for the evaluation of therapeutic target of gastric cancer.

胃癌是男性发病率显著高于女性的肿瘤之一，这种差异性的确切机制尚未阐明，研究发现胃癌的发生与雄性激素受体（AR）有相关性。AR是核受体家族成员之一 ,是配体依赖的转录活化因子。我们在前期研究中发现胃癌组织有AR与细胞周期相关激酶（Cell cycle-related kinase，CCRK）的表达，AR过表达可以上调CCRK并且促进胃癌细胞的增殖。据此我们推测AR在胃癌细胞中促进肿瘤增殖的作用是通过调控CCRK实现的。为证实这一假说，我们将采用胃癌细胞模型、胃癌动物模型，胃癌临床样本调查等方法，从体外实验-动物实验-临床调查三个层次，观察AR与CCRK表达的相关性，阐明AR活化对胃癌的发生发展的影响以及造成这种影响的分子机制，探索AR和CCRK在临床应用中的意义。为男性胃癌发病率高的特征寻找新的理论依据，并为胃癌的防治提供新的分子靶标。

胃癌是男性发病率显著高于女性的肿瘤之一，这种差异性的确切机制尚未阐明，研究发现胃癌的发生与雄性激素受体（AR）有相关性。AR 信号通路参与男性的胚胎发育，精子发生，繁殖期间雄性特异性表型的发展。并且，这种信号传导途径对于女性生殖器官的发育也具有重要意义。例如卵巢卵泡形成，胚胎植入，子宫和乳房发育等。AR属于核受体超家族中的类固醇激素受体， 类固醇激素受体是信号传导途径的关键组分，在调节基因表达中起重要作用。AR是胃癌患者的独立不良预后因素。然而，AR调节胃癌进展的机制仍不清楚。我们的研究中发现AR具有明显的促癌作用。AR在6/8 胃癌细胞系中比胃永生化细胞表达上调，并且胃癌的AR表达高于癌旁组织。此外，AR的过表达促进了胃癌细胞的集落形成能力，迁移和侵袭。相反，AR的敲低显示出对胃癌细胞的抑制作用。接下来，我们发现，在胃癌细胞中，AR通过转录调控促进CCRK表达产生促癌作用，我们在裸鼠体内实验也验证了CCRK的促癌作用。并且我们发现了AR促进胃癌的进展的分子机制是通过促进p-GSK-3β、p-β-Catenin、EGFR的表达来实现的。我们还发现AR和CCRK联合可为胃癌患者提供一个潜在的预后预测因子。