凋亡抑制分子cIAP2调控p53-EAF2协同抑制前列腺癌形成及其机制研究

More and more evidences suggest that inflammatory is closely related with the formation of PCa, but the detailed mechanism is unclear. Our preliminary assays showed that nothing was found in the prostate of p53 knockout mice, and mPIN was found in the prostate of EAF2 knockout mice. Interestingly, more than 50% of p53 and EAF2 double knockout mice had prostate cancer at 4-6 months. Then a RNA sequencing (RNA-seq) analysis was done using p53/EAF2 double knock down human prostate cancer cell line to further investigate the molecular mechanisms. cIAP2 which may play a role to trigger NF-κB pathway and a group of inflammatory factors were highly up-regulated in the double knockdown group during this RNA-seq analysis. Given that here is a hypothesis that p53 and EAF2 have a synergistic effect on tumor suppressing in prostate, and cIAP2/ NF-κB pathway may be involved in this progress. Therefore, our project is to investigate and demonstrate the function of cIAP2/ NF-κB pathway in the development of prostate cancer induced by concurrent loss of p53 and EAF2, which may provide new strategies and methods for the treatment and prevention of PCa.

前列腺癌（PCa）发生和炎症反应关系密切，但详细机制尚不清楚。抑癌基因p53和EAF2经常缺失于人PCa组织中，被认为和癌的发生密切相关。动物模型显示：单敲除p53和EAF2小鼠前列腺内没有癌形成，但双敲除小鼠前列腺内大量炎症细胞浸润并癌变，提示两者在抑制PCa形成过程中具有重要的协同作用。课题组基于双敲除模型的基因测序结果显示NFκB通路潜在调控因子cIAP2及NFκB通路的下游因子表达上调，且CXCL10等多个趋化因子和TNFα受体（TNFR1）表达上调。据此提出假设，cIAP2是p53/EAF2协同作用的关键因子，继发炎症环境的改变促进了PCa的形成。本课题拟体内观察cIAP2在p53/EAF2共缺失模型中的作用；体外研究cIAP2对NFκB通路及趋化因子的调节作用。最终阐明p53/EAF2共缺失通过cIAP2介导的炎症反应促进PCa形成的分子机制，为PCa预防和治疗提供新的策略。