Radixin介导PI3K/Akt信号通路调控自噬参与卵巢癌铂类耐药的机制研究

铂类耐药是卵巢癌死亡率居高不下的主要原因，自噬是调控铂类耐药的重要机制之一，本研究前期发现：顺铂可诱导卵巢癌细胞发生自噬，Radixin（RDX）在耐药卵巢癌组织和细胞系中表达明显升高，且与患者预后相关，干扰RDX的卵巢上皮癌耐药细胞对顺铂敏感性升高，并伴随自噬相关蛋白LC3、Beclin1、ATG5的表达下降和信号通路节点基因Akt的表达上调。据此我们提出假说：RDX具有增强卵巢上皮癌化疗敏感性的作用，并且与调控自噬通路PI3K/Akt有关。本研究拟在此基础上：1、在组织、细胞系和动物模型中研究RDX和自噬与卵巢癌铂类耐药的相关性，探讨RDX在卵巢癌铂类耐药发生中的功能和作用；2、分析验证RDX对自噬PI3K/Akt信号通路的调控模式，解析下游效应途径和靶点。本研究将从RDX调控自噬这个新视点为揭示卵巢癌铂类耐药的发生机制，为以RDX为靶点的肿瘤生物治疗奠定基础。

Platinum resistance is the main cause of the stubburnly high ovarian cancer mortality rate, autophagy is one of the important mechanisms of regulation of platinum resistance, and early discovery of this research: cisplatin induces ovarian cancer cell autophagy, RDX expression levels in ovarian cancer tissues and cell lines were significantly higher ,which also related to the prognosis; mutildrug-resistant ovarivan cancer tissue cell interfering RDX enhanced sensitivity to cisplatin, associating with decreased expression of autophagy related proteins LC3 、Beclin1、AGT5 and increasing levels of signal pathway protein Akt. Therefore, we propose the hypothesis that RDX could enhance the sensitivity of ovarian epithelial carcinoma to chemotherapy and was related to the regulation of the autophagy pathway PI3K/Akt. Based on this, this study aims to: 1.study the correlation among RDX and autophagy and platiunm resistance in ovarian cancer using tissue, cell line and animal models, and explore the function and role of Radixin in the occurrence of platinum resistance in ovarian cancer.2. analyze and verify the regulatory mode of RDX on autophagy PI3K/Akt signaling pathway, and illustrate the downstream effect pathway and target. This study will reveal the mechanism of platinum resistance in ovarian cancer from a new perspective of RDX regulating autophagy, and lay a foundation for tumor biotherapy targeting RDX.