MIIP与泛素-蛋白酶体系统（UPS）的交互调控在前列腺癌去势抵抗中的作用与机制

去势抵抗性前列腺癌（CRPC）是前列腺癌（PCa）去势治疗后的必然转归，其机制主要涉及AR再度激活及其它旁路活化。文献表明，泛素-蛋白酶体系统（UPS）通过调控AR转录活性和非AR信号通路，参与CRPC，但上游调节机制尚不清楚。MIIP是项目组早期报道的抑癌基因，我们新近研究表明：CRPC细胞系和部分PCa 患者癌组织MIIP表达降低；过表达MIIP可抑制细胞恶性行为；特别是，MIIP与蛋白酶体亚基结合并抑制UPS活性；而MIIP含量又受UPS降解调控。这些强烈提示MIIP与UPS之间存在交互调控并参与CRPC。基于此，本项目拟从细胞、分子、CRPC小鼠模型和PCa临床样本多层面，确认MIIP在CRPC中的作用；阐明MIIP调控UPS的分子机制；解析UPS 降解MIIP的功能效应；并评估上述交互调控的临床意义。本研究将丰富UPS调控理论，揭示MIIP新功能，并可能为CRPC防治提供新思路。

Castration-resistant prostate cancer (CRPC) is the inevitable outcome of the prostate cancer after androgen-deprivation therapy. The underlying mechanism involves the re-activation of AR and the activation of other by-pass pathways. According to the literatures, ubiquitin-proteasome system (UPS) is involved in CRPC through regulating the transcriptional activity of AR and AR-independent signaling pathways. Howerver, the upstream regulation of UPS in CRPC is still unknown. Our group firstly reported MIIP as a tumor suppressor gene. Most recently, we found that the expression of MIIP is downregulated in CRPC cell lines and some PCa tumor samples. Moreover,The forced expression of MIIP can inhibit the malignant behaviors in CRPC cell lines. Particularly, MIIP interacts with the proteasome subunit, PSMB5, and inhibits the activity of UPS, whereas the E3 ubiquitin ligase E6AP promotes the degradation of MIIP by the proteasome. This strongly suggests that there is a reciprocal regulation between MIIP and UPS and it is involved in CRPC. In this project, we plan to carry out the experimental study with cellular and molecular techniques, xenograft and MIIP-ko/TRAMP mouse CRPC model, as well as PCa samples analysis. We will confirm the role of MIIP in CRPC, clarify the underlying mechanism through which MIIP regulates the function of UPS, elucidate the functional effect of MIIP degradation by UPS and finally, evaluate the clinical relevance of such reciprocal regulation. This study will enrich the theroy about UPS regulation, reveal the novel function of MIIP and may provide the new throught for the prevention and treatment for CRPC.