基于APP2与Hippo信号通路在卵巢癌铂类耐药中的机制探索及靶向逆转

High metastasis and drug resistance is the key feature of ovarian cancer. The acquired tolerance of platinum-based chemotherapy has become an important cause leading to death and failure in treatment of patients with ovarian cancer. The latest highlight of the research has been involved in the molecular mechanisms of resistance and new gene therapy strategies. Based on the preliminary unpublished data, we have demonstrated that TMTP1 was specifically bound to highly metastatic ovarian tumor cells and ovarian cancer cisplatin-resistant cell in vitro and in vivo. In addition, we have identified the receptor (Aminopeptidase 2, APP2) to which TMTP1 binds at the cell surface could play the key biological effects of TMTP1. The critical biological-behavior of cisplatin drug in resisting to ovarian carcinoma may be induced by the hippo Yap pathway in which APP2 involved. Unfortunately, regarding the research of hippo Yap pathway involved in drug resistance of ovarian cancer, many areas in this field still remains vacant. We intend to initiate the research on chemo-resistance that is mediated by the cell membrane receptor APP2 which is involved in the Hippo signaling pathway in ovarian cancer. We want to confirm the mechanism of the molecular metastasis and drug resistance in ovarian cancer mediated by APP2 and Hippo signaling pathway, seperately or jointly. We also aim at the development of new antineoplastic agent made by TMTP1 and targeted gene technique that are used to reverse the chemoresistance, inhibiting recurrence and metastasis in ovarian cancer. Result of this research may provide an innovative strategy for prognosis，diagnosis and treatment of platinum resistance in ovarian cancer.

高转移和化疗耐药是卵巢癌的主要特征。其中铂类化疗的获得性耐受己成为卵巢癌患者治疗失败和死亡的重要原因，阐明其分子耐药机制并寻找新的基因作为突破点是当今研究的热点。申请人在前期已证实靶向多肽TMTP1对顺铂耐药和高转移潜能上皮性卵巢癌均具有很好的靶向性，作为TMTP1 的受体（膜表面锚定蛋白―氨肽酶P2 Aminopeptidase 2，APP2）在其中起关键生物学效应，并可能通过Hippo-YAP信号通路调控卵巢癌顺铂耐药重要生物学行为。目前关于Hippo-YAP通路在卵巢癌耐药方面的研究尚属空白，鉴于此，我们拟以APP2胞膜受体参与Hippo信号通路介导卵巢癌化疗耐药为研究主线，明确APP2与Hippo-YAP通路各自或/共同在对卵巢癌分子转移与耐药方面的调控作用，利用TMTP1与靶基因制成新型抗肿瘤制剂，用于逆转卵巢癌化疗耐药、抑制其转移复发，为卵巢癌铂类耐药的预测与诊治提供新的策略。

项目背景：高转移和化疗耐药是卵巢癌的主要特征。其中铂类化疗的获得性耐受己成为卵巢癌患者治疗失败和死亡的重要原因，阐明其分子耐药机制并寻找新的基因作为突破点是当今研究的热点。申请人在前期已证实靶向多肽TMTP1对顺铂耐药和高转移潜能上皮性卵巢癌均具有很好的靶向性，作为TMTP1 的受体（膜表面锚定蛋白―氨肽酶P2 Aminopeptidase 2，APP2）在其中起关键生物学效应，并可能通过Hippo-YAP信号通路调控卵巢癌顺铂耐药重要生物学行为。主要研究内容：明确APP2与Hippo信号通路各自或/共同在对卵巢癌分子转移与耐药方面的调控作用，为探寻调控Hippo-YAP基因表达的下游信号分子提供实验依据，并为卵巢癌铂类耐药的预测与诊治提供一种全新的策略。重要结果、关键数据及其科学意义：我们发现 APP2 在耐药的卵巢癌细胞C13K 以及高转移的卵巢癌细胞 SKOV3.ip 明显高于其配对的细胞。此外APP2在不同转移潜能的肿瘤组织有表达差异性，提示APP2可能肿瘤转移明侵袭相关的一个新标志物；同时APP2能很好的识别卵巢癌耐药细胞，这为靶向阻遏卵巢癌的耐药提供了切实可行的方法；另一方面，我们初步筛选出卵巢癌耐药关键靶基因YAP、TAZ和14-3-3zeta，并在体外实验进行了初步的功能验证。利用TMTP1与靶基因制成新型抗肿瘤制剂，并在体内外验证了其对卵巢癌的靶向阻遏效应；为卵巢癌铂类耐药的预测与诊治提供新的策略。