MiR-487a resensitizes mitoxantrone (MX)-resistant breast cancer cells (MCF-7/MX) to MX by targeting breast cancer resistance protein (BCRP/ABCG2)
MiR-487a resensitizes mitoxantrone (MX)-resistant breast cancer cells (MCF-7/MX) to MX by targeting breast cancer resistance protein (BCRP/ABCG2)
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MiR-487a 通过靶向乳腺癌耐药蛋白 (BCRP/ABCG2) 使米托蒽醌 (MX) 耐药乳腺癌细胞 (MCF-7/MX) 对 MX 重新敏感
DOI：
10.1016/j.canlet.2013.07.016
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发表时间：
2013-10-01
期刊：
影响因子：
9.7
通讯作者：
Wei, Min-Jie
中科院分区：
文献类型：
--
作者：
Ma, Meng-Tao;He, Miao;Wei, Min-Jie
乳腺癌耐药蛋白（BCRP/ABCG 2）特异性转运多种化疗药物，并参与癌细胞多药耐药（MDR）的形成。微小RNA（miRNAs）在调节癌细胞对化疗剂的敏感性中可以发挥重要作用。因此，在证实BCRP在米托蒽醌（MX）耐药的MCF-7乳腺癌细胞系MCF-7/MX中比其亲本敏感的MCF-7细胞系增加后，我们的目的是探索调节BCRP表达并使乳腺癌细胞对化疗药物敏感的miRNA。生物信息学分析表明，miR-487 a是与BCRP的3'非翻译区（3' UTR）结合的miRNAs之一。定量RT-PCR（qRT-PCR）分析表明，MCF-7/MX细胞中miR-487 a的表达减少，荧光素酶报告基因试验表明，miR-487 a直接结合BCRP的3 'UTR。此外，异位miR-487 a在mRNA和蛋白水平下调BCRP表达，增加耐药MCF-7/MX乳腺癌细胞中MX的细胞内蓄积和细胞毒性。同时，抑制miR-487 a可在mRNA和蛋白水平上增加BCRP表达，并诱导敏感MCF-7乳腺癌细胞对MX产生耐药性。此外，在用miR-487 a agmir处理的MCF-7/MX异种移植肿瘤中也检测到BCRP表达减少和MX抗肿瘤作用增加。因此，我们的研究结果表明，miR-487 a可以直接调节BCRP表达，并逆转乳腺癌亚组的化疗药物耐药性。(C)2013爱思唯尔爱尔兰有限公司版权所有。
Breast cancer resistance protein (BCRP/ABCG2) specifically transports various chemotherapeutic agents and is involved in the development of multidrug resistance (MDR) in cancer cells. MicroRNAs (miRNAs) can play an important role in modulating the sensitivity of cancer cells to chemotherapeutic agents. Therefore, after confirming that BCRP was increased in the mitoxantrone (MX)-resistant MCF-7 breast cancer cell line MCF-7/MX compared with its parental sensitive MCF-7 cell line, we aimed to explore the miRNAs that regulate BCRP expression and sensitize breast cancer cells to chemotherapeutic agents. In the present study, bioinformatic analysis indicated that miR-487a was one of the miRNAs that could bind to the 3' untranslated region (3'UTR) of BCRP. Quantitative RT-PCR (qRT-PCR) analysis demonstrated that the expression of miR-487a was reduced in MCF-7/MX cells, and a luciferase reporter assay demonstrated that miR-487a directly bound to the 3'UTR of BCRP. Moreover, ectopic miR-487a down-regulated BCRP expression at the mRNA and protein levels, increasing the intracellular accumulation and cytotoxicity of MX in resistant MCF-7/MX breast cancer cells. Meanwhile, inhibition of miR-487a increased BCRP expression at the mRNA and protein levels and induced MX resistance in sensitive MCF-7 breast cancer cells. Furthermore, the reduced expression of BCRP and increased antitumor effects of MX were also detected in MCF-7/MX xenograft tumors treated with the miR-487a agmir. Thus, our results suggested that miR-487a can directly regulate BCRP expression and reverse chemotherapeutic drug resistance in a subset of breast cancers. (C) 2013 Elsevier Ireland Ltd. All rights reserved.