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MicroRNA-302 represses epithelial-mesenchymal transition and cisplatin resistance by regulating ATAD2 in ovarian carcinoma.
Experimental Cell Research ( IF 3.7 ) Pub Date : 2020-08-21 , DOI: 10.1016/j.yexcr.2020.112241
Tingting Ge 1 , Tianbo Liu 1 , Liyuan Guo 1 , Zhuo Chen 2 , Ge Lou 1
Affiliation  

Epithelial-mesenchymal transition (EMT) is an important contributor to drug resistance in ovarian cancer. The aims of this study were to explore the potential role of the miR-302 cluster in modulating EMT and cisplatin resistance in ovarian cancer. We used qRT-PCR and western blotting to show that miR-302 expression was lower in chemoresistant than in chemosensitive cells, and miR-302 was upregulated in chemosensitive, but not chemoresistant ovarian cancer cells in response to cisplatin treatment. We identified ATAD2 as a target of miR-302 and showed that ectopic expression of miR-302 increased cisplatin sensitivity and inhibited EMT and the invasiveness of cisplatin-resistant cells in vitro by targeting ATAD2. Knockdown of ATAD2 restored cisplatin sensitivity and reversed EMT/metastasis in cisplatin-resistant cells, as shown by western blotting and invasion/migration assays. The effect of miR-302 overexpression on EMT and invasiveness was mediated by the modulation of β-catenin nuclear expression. Immunofluorescence analysis showed that ATAD2 overexpression reversed the miR-302-induced downregulation of nuclear β-catenin in cisplatin resistant cells. A xenograft tumor model was used to show that miR-302 increases the antitumor effect of cisplatin in vivo. Taken together, these results identify a potential regulatory axis involving miR-302 and ATAD2 with a role in chemoresistance, indicating that activation of miR-302 or inactivation of ATAD2 could serve as a novel approach to reverse cisplatin resistance in ovarian cancer.



中文翻译:

MicroRNA-302通过调节ATAD2在卵巢癌中抑制上皮-间质转化和顺铂耐药性。

上皮-间质转化(EMT)是卵巢癌耐药性的重要因素。这项研究的目的是探讨miR-302簇在调节卵巢癌EMT和顺铂耐药性中的潜在作用。我们使用qRT-PCR和Western印迹法显示,化学反应中的miR-302表达低于化学敏感细胞,而对化学敏感的miR-302表达上调,但对顺铂处理无反应的卵巢癌细胞却未上调。我们确定ATAD2为miR-302的靶标,并表明miR-302的异位表达增加了顺铂敏感性,并抑制了EMT和顺铂耐药细胞的体外侵袭性通过定位ATAD2。免疫印迹和侵袭/迁移分析表明,敲除ATAD2可恢复顺铂敏感性细胞中的顺铂敏感性,并逆转EMT /转移。miR-302过表达对EMT和侵袭性的影响是由β-catenin核表达的调节介导的。免疫荧光分析表明,ATAD2的过表达逆转了miR-302诱导的顺铂耐药细胞中核β-连环蛋白的下调。使用异种移植肿瘤模型显示miR-302在体内增强顺铂的抗肿瘤作用。综上所述,这些结果确定了涉及miR-302和ATAD2并具有化学抗性的潜在调控轴,这表明miR-302的激活或ATAD2的失活可以作为逆转卵巢癌顺铂耐药性的新方法。

更新日期:2020-08-29
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