LncRNA LINC00115及circRNA CDR1as竞争结合miR-7调控ERK/MAPK和 mTOR信号通路在卵巢癌顺铂耐药中的作用研究

Cisplatin resistance affects the prognosis of ovarian cancer seriously. MiR-7 can reverse drug resistance in a variety of tumors, while its correlation with drug resistance of ovarian cancer is unknown. The ectopic activation of ERK/MAPK and mTOR signaling pathways can promote cisplatin resistance of ovarian cancer. The preliminary experiment results show a significantly low expression of miR-7 in ovarian cancer tissues and cells of cisplatin resistance and a high expression of lncRNA LINC00115, circRNA CDR1as, ERK and mTOR. Bioinformatics predicted that the RNAs of these four molecules possess miR-7 binding sites. We speculate that the competitive combination between LINC00115&CDR1as and miR-7 can activate the ERK/MAPK and mTOR signaling pathways, which may promote the cisplatin resistance of ovarian cancer. This study plan to explore the regulating relation and effect of LINC00115&CDR1as/miR-7/ERK&mTOR axis in cisplatin resistance of ovarian cancer, via gene transfection, from three levels of tissues, cells and animal models. This project intends to study the pathogenesis of cisplatin resistance in ovarian cancer, explore active molecules and therapeutic targets that can predict the risk of cisplatin resistance, provide the basis for the application of clinical transformation.

顺铂耐药严重影响卵巢癌预后；miR-7在多种肿瘤中能逆转耐药，但与卵巢癌耐药相关性未知；ERK/MAPK和mTOR通路异常激活能促进卵巢癌顺铂耐药的发生。预实验结果显示，miR-7在卵巢癌顺铂耐药组织及细胞中表达明显降低，而lncRNA LINC00115、circRNA CDR1as、ERK和mTOR蛋白表达则显著增高；经生物信息学方法预测，这4个分子的RNA均具有miR-7结合位点。我们推测：LINC00115和CDR1as 能通过竞争结合miR-7激活ERK/MAPK和mTOR通路，促进卵巢癌顺铂耐药的发生。本课题拟在组织、细胞和动物模型3个实验水平，借助基因转染技术，探索LINC00115&CDR1as/miR-7/ERK&mTOR轴在卵巢癌顺铂耐药中的调控关系及调控效应。本项目拟深入研究卵巢癌顺铂耐药的发生机制，探寻能提示耐药风险的活性分子及治疗靶点，为其临床转化应用提供依据。

顺铂化疗耐药严重影响着卵巢癌患者的预后和生存。miR-7可作为抑癌基因调控增殖、侵袭及耐药，但其在卵巢癌顺铂耐药中尚无报道。预实验结果显示，miR-7在卵巢癌顺铂耐药组织及细胞中表达降低，经预测ERK为其重要靶基因。lncRNA LINC00115和circRNA CDR1as具有miR-7结合位点，可能影响其表达。在卵巢癌顺铂耐药组织及细胞中，LINC00115显著增高。我们推测miR-7受LINC00115的调控，可激活ERK/MAPK通路，导致卵巢癌细胞顺铂耐药。研究表明，circRNA CDR1as 在生物学上与大量癌症有关。然而，CDR1as 在卵巢癌中顺铂耐药的作用机制仍不清楚。我们发现与正常卵巢组织相比，CDR1as在卵巢癌组织中下调；与卵巢癌顺铂敏感细胞相比，CDR1as在卵巢癌顺铂耐药细胞中也显著下调。因此，我们推测CDR1as也参与了卵巢癌顺铂耐药。本课题拟在组织、细胞和动物模型中探讨LINC00115/miR-7/ERK调节轴及CDR1as在卵巢癌顺铂耐药中的作用机制，解析LINC00115/miR-7和CDR1as调节顺铂耐药的方式，及其介导的通路和效应。在本研究中，我们深入研究LINC00115/miR-7及CDR1as在卵巢癌顺铂耐药的作用机制，通过特定分子标志提示耐药风险，为其转化应用奠定基础。