miR-29c-3p inhibits autophagy and cisplatin resistance in ovarian cancer by regulating FOXP1/ATG14 pathway
miR-29c-3p inhibits autophagy and cisplatin resistance in ovarian cancer by regulating FOXP1/ATG14 pathway
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DOI：
10.1080/15384101.2019.1704537
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发表时间：
2019-12-26
期刊：
影响因子：
4.3
通讯作者：
Guo, Ruixia
中科院分区：
文献类型：
--
作者：
Hu, Zhenhua;Cai, Mingbo;Guo, Ruixia
自噬，以自噬相关基因14 （ATG14）的提升和自噬相关蛋白的失调为特征，有助于卵巢癌顺铂（DDP）耐药。叉头盒蛋白P1 （FOXP1）是一种定义明确的转录因子，据报道在卵巢癌中具有致癌作用。本研究旨在确定miR-29c-3p/FOXP1/ATG14通路在卵巢癌自噬和DDP耐药中的调节作用。检测miR-29c-3p、FOXP1、ATG14和自噬相关蛋白在DDP敏感卵巢癌细胞系（SKOV3和A2780）和耐DDP细胞系（SKOV3/DDP和A2780/DDP）中的表达。采用MTT法检测细胞活力。在裸鼠异种移植瘤模型中观察miR-29c-3p过表达的治疗效果。与ddp敏感细胞相比，ddp耐药细胞中miR-29c-3p降低，ddp耐药细胞中FOXP1、ATG14、自噬和耐药性增强。我们观察到miR-29c-3p的抗耐药作用，过表达miR-29c-3p抑制ddp耐药细胞的细胞活力。此外，FOXP1是miR-29c-3p的靶标，通过荧光素酶报告基因实验证实了这一点，并且通过ChIP实验证实了ATG14被FOXP1反激活。过表达miR-29c-3p通过下调FOXP1/ATG14在体外增加DDP敏感性。体内注射过表达mir -29c-3p的SKOV3/DDP细胞后，肿瘤体积减小。过表达miR-29c-3p部分通过下调FOXP1/ATG14通路抑制自噬和DDP耐药，提示miR-29c-3p是克服卵巢癌DDP耐药的新靶点。
Autophagy, characterized by the elevator of autophagy-related gene 14 (ATG14) and the dysregulation of autophagy-related proteins, contributes to the cisplatin (DDP) resistance in ovarian cancer. Forkhead box protein P1 (FOXP1), which is a well-defined transcription factor, is reported to have the oncogenic effect on ovarian cancer. This study aims to identify the effect of miR-29c-3p/FOXP1/ATG14 pathway in regulating autophagy and DDP resistance in ovarian cancer. The expressions of miR-29c-3p, FOXP1, ATG14 and autophagy-related proteins were detected in DDP-sensitive ovarian cancer cell lines (SKOV3 and A2780) and DDP-resistant cell lines (SKOV3/DDP and A2780/DDP). Cell viability was detected using the MTT assay. The therapeutic effect of miR-29c-3p overexpression was observed in the xenograft model of nude mice.Compared with DDP-sensitive cells, miR-29c-3p was decreased in DDP-resistant cells, and an enhancement of FOXP1, ATG14, autophagy, and drug resistance was shown in DDP-resistant cells. The anti-resistant effect of miR-29c-3p was observed as overexpressing miR-29c-3p inhibited cell viability of DDP-resistant cells. Moreover, FOXP1 was a target of miR-29c-3p, which was confirmed by the luciferase reporter assay, and ATG14 was transactivated by FOXP1, which was confirmed by the ChIP assay. Overexpression of miR-29c-3p increased DDP sensitivity by downregulating FOXP1/ATG14 in vitro. The tumor volume was reduced after the injection of miR-29c-3p-overexpressing SKOV3/DDP cells in vivo. Overexpression of miR-29c-3p inhibited autophagy and DDP resistance partly via downregulating FOXP1/ATG14 pathway, suggesting miR-29c-3p as a novel target in overcoming DDP resistance in ovarian cancer.