COPS5在上皮性卵巢癌铂类耐药中的作用及其机制研究

铂类化疗是目前上皮性卵巢癌（EOC）重要的治疗手段。有激酶功能的光调蛋白9的第五亚基（COPS5）在卡铂耐受的EOC中表达水平显著升高，通过内质网应激变化和磷酸化作用使XBP1、p27等表达发生改变，影响到铂类化疗的敏感性。本课题前期工作发现，COPS5下调后，XBP1和p27水平升高，耐药细胞增殖、生长能力显著降低，提示COPS5下调可逆转化疗的耐受性，相关机制尚不清楚。本项目拟以卡铂耐受EOC细胞的“COPS5-IRE1/XBP1-UPR”和“COPS5-p-Akt-p27”两条信号通路为主线，采用生物信息学手段、CO-IP、蛋白芯片、细胞代谢分析等技术，在临床肿瘤标本、细胞模型、体内实验等多层次上，研究COPS5表达水平与EOC卡铂耐受之间的关系，阐明COPS5在卡铂耐受EOC应激、增殖、生长中的具体作用，为揭示铂类化疗耐药机制提供新思路，也为临床上EOC患者采取个体化治疗奠定基础。

Chemotherapy with platinum agents remains the necessary treatment of epithelial ovarian cancer (EOC). The expression level of kinase-like COPS5 (Constitutive Photomorphogenic Signalosome 9 Subunit 5) rises significantly in carboplatin-resistant EOC patients, consequently, the levels of XBP1 and p27 were regulated by endoplasmic reticulum (ER) stress and cell phosphorylation, respectively; has a direct impact on the sensitivity of platinum-containing drugs chemohtherapy. In our previous studies, we found that the levels of XBP1 and p27 were elevated by down-regulation of COPS5 in carboplatin-resistant EOC cells, the proliferation and growth of these cells were suppressed, which indicated that the inhibition of COPS5 can reverse the resistance of carboplatin-resistance. However, the mechanism still remains unclear. This project will focus on two pathways including the “COPS5-pAkt-p27” and “COPS5-IRE1/XBP1-UPR” in carboplatin-resistant EOC cells. We further investigate the associations between the overexpression of COPS5 and carboplatin-resistance in EOC by bioinformatics, CO-IP, protein interaction chip and cell metabolism analysis etc and illustrate the impact of COPS5 on cell stress, proliferation and growth in carboplatin-resistance EOC cells using the clinical specimens and cell models in vitro and in vivo. This project will provide a novel view in the mechanism of chemotherapy-resistance with platinum agents, and lay the foundation of the personalized management for EOC patients.