LincPINT调节miR335/FANCA 轴引起上皮性卵巢癌化疗耐药的机制研究

化疗耐药是肿瘤复发致死的关键因素，在卵巢癌中尤为明显。在前期研究中，我们发现miR335低表达与卵巢癌化疗耐药相关。下调miR335通过FANCA/BRCA1通路激活同源重组修复使肿瘤细胞逃避化疗药物杀伤作用。且发现lincPINT能下调miR335。因此我们推测，lincPINT通过海绵吸附作用竞争性结合miR335，使其转录后调控FANCA抑制作用减弱，加速BRCA1/FANCA复合体募集至DNA损伤部位激活同源重组修复通路HR引起卵巢癌顺铂耐药。本研究将通过生物信息学分析，RNA pull-down，双荧光素酶报告及耐药相关实验，阐明lincPINT/miR335/FANCA轴对于DNA损伤修复引起卵巢癌化疗耐药内在作用机理进行逐步验证。本研究通过阐明lincPINT下调miR335激活同源重组修复引起化疗耐药的分子机制，为改善卵巢癌预后提供理论依据。

Chemotherapy drug resistance is the critical factor for tumor death and recurrence, especially in ovarian cancer. In previous studies, we found that low expression of miR335 was associated with chemotherapy drug resistance in ovarian cancer. Down-regulated miR335 activates homologous recombinant repair through the FANCA/BRCA1 pathway, and enabling tumor cells to escape the killing effect of chemotherapy drugs. and lincPINT could reduce the expression of miR335. Therefore, we speculate that lincPINT can downregulate miR335 through post-transcriptional regulation,as a competitive endogenous RNA (ceRNA) that binds to microRNA (miRNA) through a “sponge” adsorption mechanism，reduce the inhibitory effect of FANCA by affecting the homologous recombination DNA damage repair, and enhance DNA damage repair in cisplatin-resistant ovarian tumors. This study predicted, by using bioinformatics, RNA pull-down experiment, Dual Luciferase Reporter Assay and drug resistance related experiments; the expression of miR335 and chemotherapy drug resistance of ovarian tumors correlation to clarify the progressive verification of the internal mechanism of lincPINT/miR335/FANCA axis for DNA damage repair and chemotherapy resistance of ovarian cancer. This study clarified the molecular mechanism of response lincPINT downregulating miR335 and inducing DNA damage repair in chemotherapy resistant ovarian cancer, and provided more theoretical basis for the improved treatment of chemoresistant ovarian cancer.