SOX4在去势抵抗性前列腺癌中的作用及其机制研究

项目名称： SOX4在去势抵抗性前列腺癌中的作用及其机制研究

项目编号： No.81472417

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 韩博

作者单位： 山东大学

项目金额： 75万元

中文摘要： 去势抵抗性前列腺癌（CRPC）是前列腺癌（PCa）治疗领域的难点，患者预后差。SOX4基因是参与胚胎发育和干细胞维持的转录因子，在多种恶性肿瘤中过表达。本课题组前期报道了SOX4可与其它癌基因协同促进PCa的侵袭和转移。最近我们发现，SOX4在CRPC组织、长期雄激素剥夺条件下的PCa细胞和其诱导生成的肿瘤干细胞中表达水平均显著升高,提示SOX4可能通过雄激素受体(AR)依赖和AR非依赖（涉及肿瘤干细胞形成/维持）途径参与CRPC的发生和发展。为阐明SOX4在CRPC中的作用和机制，本课题拟分析SOX4在CRPC中过表达的病理学特征和分子机制；体内外实验观察SOX4在CRPC发生发展中的生物学功能及与雄激素-AR通路的关系；研究SOX4对PCa肿瘤干细胞形成、维持及自我更新的作用；系统筛选SOX4调控的靶基因和miRNA；整合并建立CRPC中SOX4表达相关的转录程序及个性化调控网络。

中文关键词： SOX4；去势抵抗性；前列腺癌；肿瘤干细胞

英文摘要： Castration-resistant prostate cancer (CRPC) has an extremely poor prognosis and remains a significant clinical challenge as the underlying mechanisms are largely unknown. The SOX4 transcription factor is involved in the development, maintenance of stem cell and cell fate decision. Overexpression of SOX4 has been identified in multiple cancers. Previously, our group has reported that SOX4 may collaborate with other oncogenes to promote PCa invasion and metastasis. Most recently, we found that the expression levels of SOX4 increases significantly in both CRPC tissues and PCa cells when placed under long-term androgen-deprivation condition. Furthermore, SOX4 expression was also up-regulated in the induced PCa stem cells. These data suggest that SOX4 may promote CRPC progression through androgen receptor (AR) dependent as well as AR independent ways (induction/maintenance of tumor stem cell). To define the roles of SOX4 in CRPC, our project is intended to: 1) characterize the clinico-pathological features of SOX4+ subtype PCa and mechanisms of SOX4 overexpression in CRPC. 2) determine the biological functions of SOX4 in CRPC and interactions between SOX4 and androgen-AR signaling pathway in vitro and in vivo. 3) evaluate the role of SOX4 in the induction, maintenance and self-renewal of PCa stem cells in CRPC. 4) systematically screen and identify the potentially targeted genes and miRNAs of SOX4. 5) establish transcription program and individualized regulation network of SOX4 expressions in CRPC.

英文关键词： SOX4;Castration-resistant;Prostate cancer;Cancer stem cell