Abstract：
Ovarian cancer (OC) is a devastating disease for women, with chemotherapy resistance taking the lead. Cisplatin has been the first-line therapy for OC for a long time. However, the resistance of OC to cisplatin is an important impediment to its efficacy. Mounting studies showed that ovarian cancer stem cells (OCSCs) affected chemotherapy resistance by secreting exosomes. MicroRNAs (miRNAs) play important roles in exosomes secreted by OCSCs. Here, through the analysis of GEO database (GSE107155) combined with RT-qPCR of OC-related cells/clinical tissues, it was found that hsa-miR-4516 (miR-4516) was significantly up-regulated in OCSCs. Then, OCSCs-derived exosomes were isolated and identified, and it was observed the influence of exosomes on the chemoresistance in SKOV3/cisplatin (SKOV3/DDP) cells. These results manifested that OCSCs-mediated exosomes facilitated the chemoresistance of SKOV3/DDP cells by delivering miR-4516 into them. Growth arrest-specific 7 (GAS7), a downstream target of miR-4516, was determined by bioinformatics prediction combined with molecular biological detection. Next, we up-regulated GAS7 expression and discovered that the promotion of chemoresistance in SKOV3/DDP cells by OCSCs-derived exosomes was significantly impaired. Finally, the mice tumor model of SKOV3/DDP cells was built to estimate the effect of GAS7 over-expression on OC growth. The results showed that GAS7 inhibited the chemoresistance of OC in vivo. In conclusion, our experiments suggested that OCSCs-derived exosomes enhanced OC cisplatin resistance by suppressing GAS7 through the delivery of miR-4516. This study provides a possible target for the treatment of OC DDP resistance.
摘要：
卵巢癌（OC）对女性来说是一种毁灭性的疾病，化疗抵抗带头。顺铂长期以来一直是OC的一线治疗。然而,OC对顺铂的耐药性是其疗效的重要障碍。越来越多的研究表明，卵巢癌干细胞（OCSCs）通过分泌外泌体影响化疗耐药性。MicroRNAs(miRNA)在OCSCs分泌的外泌体中发挥重要作用。这里,通过GEO数据库(GSE107155)结合OC相关细胞/临床组织的RT-qPCR分析,发现hsa-miR-4516(miR-4516)在OCSCs中显著上调。然后，分离并鉴定OCSCs来源的外泌体，观察外泌体对SKOV3/顺铂（SKOV3/DDP）细胞化疗耐药的影响。这些结果表明，OCSC介导的外泌体通过将miR-4516递送到SKOV3/DDP细胞中促进了它们的化学抗性。生长停滞特异性7（GAS7），通过生物信息学预测结合分子生物学检测确定miR-4516的下游靶标。接下来,我们上调GAS7的表达,发现OCSCs来源的外泌体对SKOV3/DDP细胞化疗耐药的促进作用明显受损.最后,建立SKOV3/DDP细胞的小鼠肿瘤模型，以评估GAS7过表达对OC生长的影响。结果表明，GAS7在体内抑制OC的化学抗性。总之,我们的实验表明,OCSCs来源的外泌体通过递送miR-4516抑制GAS7增强OC顺铂耐药.本研究为OC一DDP耐药的治疗提供了可能的靶点。
