Reversal of cisplatin resistance by microRNA-139-5p-independent RNF2 downregulation and MAPK inhibition in ovarian cancer
Reversal of cisplatin resistance by microRNA-139-5p-independent RNF2 downregulation and MAPK inhibition in ovarian cancer
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DOI：
10.1152/ajpcell.00283.2017
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发表时间：
2018-08-01
影响因子：
5.5
通讯作者：
Wang, Hui
中科院分区：
文献类型：
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作者：
Chen, Ying;Cao, Xiao-Yun;Wang, Hui
一些microRNAs(MiRs)在癌症中调节失调，miR的异常表达与癌细胞的化疗耐药有关。因此。本研究旨在探讨microRNA139-5p(miR-139-5p)通过环指蛋白2(RNF2)和丝裂原活化蛋白激酶(MAPK)信号通路对卵巢癌顺铂耐药的影响。OC组织取自66例原发OC患者。收集顺铂敏感的A2780和顺铂耐药的A2780/DDP细胞株，构建RNF2沉默和高表达载体。用四甲基偶氮唑蓝(3-(4，5-dimethylthiazol-2-yl)-2，5-diphenyltetrazolium)比色法检测细胞活力，Annexin V-FITC/碘化丙啶双染色法检测细胞凋亡率。通过定量逆转录-定量聚合酶链式反应和Western印迹分析检测RNF2和p38的表达。最后测定BALB/c裸鼠移植瘤体积。RNF2和miR-139-5p参与了卵巢癌的发生。此外。MAPK活化和RNF2与卵巢癌顺铂耐药有关。在顺铂耐药的OC组织中，miR-139-5p表达下调，miR-139-5p过表达可抑制细胞活力，降低对顺铂的耐药性，促进OC细胞的凋亡。此外，miR-139-5P与MAPK抑制剂联合应用能更明显地降低OC对顺铂的耐药性。综上所述，本研究证明miR-139-5p的过度表达和MAPK信号通路的失活可以通过抑制RNF2来逆转OC对顺铂的耐药性。因此，miR-139-5p过表达可能成为卵巢癌未来的治疗策略。
Some microRNAs (miRs) are dysregulated in cancers, and aberrant miR expression has been reported to correlate with chemoresistance of cancer cells. Therefore. the present study aims at investigating the effects of microRNA139-5p (miR-139-5p) on cisplatin resistance of ovarian cancer (OC) with involvement of ring finger protein 2 (RNF2) and the mitogen-activated protein kinase (MAPK) signaling pathway. OC tissues were obtained from 66 primary OC patients. The cisplatin-sensitive A2780 and cisplatin-resistant A2780/DDP cell lines were collected for construction of RNF2 silencing and overexpressed plasmids. Cell vitality and apoptosis were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and annexin V-FITC/propidium iodide double-staining, respectively. Next, expression of RNF2, extracellular signal-related kinase, and p38 was determined by quantitative reverse transcription-quantitative polymerase chain reaction and Western blot analysis. Finally, the volume of xenograft tumors in BALB/c nude mice was detected. RNF2 and miR-139-5p were identified to be involved in OC. In addition. MAPK activation and RNF2 were related to cisplatin resistance of OC. miR-139-5p was downregulated in cisplatin-resistant OC tissues, and miR-139-5p overexpression could inhibit cell vitality, reduce cisplatin resistance, and promote apoptosis of OC cells. Furthermore, miR-139-5p combined with MAPK inhibitors more obviously reduced cisplatin resistance of OC. Taken together, this study demonstrated that miR-139-5p overexpression combined with inactivation of the MAPK signaling pathway can reverse the cisplatin resistance of OC by suppressing RNF2. Thus, miR-139-5p overexpression might be a future therapeutic strategy for OC.