MiR-129-3p promotes docetaxel resistance of breast cancer cells via CP110 inhibition.
MiR-129-3p promotes docetaxel resistance of breast cancer cells via CP110 inhibition.
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MiR-129-3p 通过抑制 CP110 促进乳腺癌细胞的多西紫杉醇耐药性。
DOI：
10.1038/srep15424
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发表时间：
2015-10-21
影响因子：
4.6
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Zhang Y;Wang Y;Wei Y;Li M;Yu S;Ye M;Zhang H;Chen S;Liu W;Zhang J
多西紫杉醇作为一种有效的化疗药物被广泛用于乳腺癌的治疗，但其耐药机制尚不完全清楚。本研究的目的是探讨miR-129-3p在乳腺癌细胞对多西他赛耐药中的可能作用。将miR-129和miR-129-3p抑制剂分别导入乳腺癌细胞，观察其对多西他赛化疗耐药的影响。通过细胞凋亡、细胞增殖和细胞周期检测来评价miR-129-3p的功能。我们发现，与亲本细胞相比，在MDA-MB-231/Doc细胞中miR-129-3p表达上调，同时CP110表达下调。体外药敏实验表明，miR-129-3p抑制能使MDA-MB-231/Doc和MCF-7细胞对多西紫杉醇增敏，而miR-129过表达则增加了细胞对多西紫杉醇的耐药性。在MDA-MB-231细胞中，异位miR-129表达降低了CP110的表达和CP110 3‘非翻译区报告结构的荧光素酶活性，表明CP110是一个直接的miR-129-3p靶标。我们证明，通过miR-129过表达恢复了MDA-MB-231和MCF-7细胞中CP110的表达，使细胞对多西紫杉醇敏感。在裸鼠移植瘤模型中，miR-129上调显著降低了MDA-MB-231细胞对多西紫杉醇的反应。我们的发现表明，miR-129-3p下调可能会使乳腺癌细胞对多西他赛治疗敏感。
Docetaxel is commonly used as an effective chemotherapeutic agent in breast cancer treatment, but the underlying mechanisms of drug resistance are not fully understood. The purpose of this study was to investigate the possible role of miR-129-3p in breast cancer cell resistance to docetaxel. MiR-129 and miR-129-3p inhibitor were transfected into breast cancer cells to investigate their effects on chemoresistance to docetaxel. The function of miR-129-3p was evaluated by apoptosis, cell proliferation, and cell cycle assays. We found that miR-129-3p was up-regulated in MDA-MB-231/Doc cells, concurrent with CP110 down-regulation, compared to the parental MDA-MB-231 cells. In vitro drug sensitivity assays demonstrated that miR-129-3p inhibition sensitized MDA-MB-231/Doc and MCF-7 cells to docetaxel, whereas miR-129 overexpression enhanced MDA-MB-231 and MCF-7 cell resistance to docetaxel. Ectopic miR-129 expression reduced CP110 expression and the luciferase activity of a CP110 3′ untranslated region-based reporter construct in MDA-MB-231 cells, suggesting that CP110 is a direct miR-129-3p target. We demonstrated that restoration of CP110 expression in MDA-MB-231 and MCF-7 cells by miR-129 overexpression rendered the cells sensitive to docetaxel. In a nude xenograft model, miR-129 up-regulation significantly decreased MDA-MB-231 cells’ response to docetaxel. Our findings suggest that miR-129-3p down-regulation potentially sensitizes breast cancer cells to docetaxel treatment.