EAF2表达缺失改变局部微环境促进去势抵抗性前列腺癌形成机制的研究

项目名称： EAF2表达缺失改变局部微环境促进去势抵抗性前列腺癌形成机制的研究

项目编号： No.81502212

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 郭文焕

作者单位： 上海交通大学

项目金额： 16万元

中文摘要： 去势抵抗性前列腺癌（CRPC）临床治疗棘手。越来越多的证据表明，CRPC形成与肿瘤炎性微环境关系密切，但详细机制尚不清楚。课题组前期研究发现肿瘤抑制因子EAF2基因敲除小鼠前列腺间质内大量炎症细胞浸润，且前列腺上皮细胞对去势治疗敏感性下降。干扰前列腺癌细胞中EAF2表达可增强巨噬细胞迁移能力，并导致CCL2、CCL5等多种趋化因子以及白介素6受体上调。据此我们提出假设：EAF2表达缺失可能通过改变肿瘤局部炎性微环境促进CRPC的形成。本课题拟体外观察EAF2表达变化对前列腺癌细胞对激素敏感性以及激素撤除耐受性的影响，研究EAF2对趋化因子的调控作用及机制，探讨IL-6/IL-6R系统在其中的介导作用；并在动物实验及临床组织标本两个层面进行进一步验证。最终阐明EAF2表达缺失在CRPC形成过程中的作用及其分子机制，为CRPC的治疗提供新的策略和方法。

中文关键词： 前列腺肿瘤；EAF2；微环境；炎症；白介素6

英文摘要： The treatment of Castration resistant prostate cancer (CRPC) is a big challenge in clinical medicine. More and more evidence suggests that inflammatory microenvironment is closely related with the formation of CRPC, but the detailed mechanism is unclear. Our previous study found that tumor suppressor gene EAF2 knockout mice had increased stromal inflammatory cell infiltrating and decreased sensitivity of prostate epithelial cells to androgen deprivation therapy. Furthermore, knockdown of EAF2 expression in prostate cancer cells can promote the migration of macrophages, and lead to secretion of many chemokines, as well as IL-6 receptor up-regulation. Based on above results, we hypothesize: Loss of EAF2 probably promote the formation of CRPC by regulating local inflammatory microenvironment in tumor. In this project, we try to observe the effect of EAF2 on prostate cancer cells sensitivity to androgen and resistance to withdrawal of androgen, study the role and mechanism of EAF2 in regulating chemokines expression and explore the mediator function of IL-6 / IL-6R pathway in formation of CRPC. Finally, we will further confirm our results using both animal experiments and clinical tissue samples. The ultimate goal of this project is to clarify the role of EAF2 in formation of CRPC and the underlying mechanism and provide new strategies and methods for the treatment of CRPC.

英文关键词： prostate cancer;EAF2;microenvironment;inflammation;Interleukin-6