Zhang Yuan, Wang Yu, Wei Yifang, Li Mengyang, Yu Shentong, Ye Mingxiang, Zhang Hongmei, Chen Suning, Liu Wenchao, Zhang Jian
The State Key Laboratory of Cancer Biology and Department of Oncology, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
The State Key Laboratory of Cancer Biology and Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an 710032, China.
Sci Rep. 2015 Oct 21;5:15424. doi: 10.1038/srep15424.
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.
多西他赛是乳腺癌治疗中常用的一种有效化疗药物，但耐药的潜在机制尚未完全明确。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抑制剂转染至乳腺癌细胞中，以研究它们对多西他赛化疗耐药性的影响。通过凋亡、细胞增殖和细胞周期检测来评估miR-129-3p的功能。我们发现，与亲代MDA-MB-231细胞相比，MDA-MB-231/Doc细胞中miR-129-3p上调，同时CP110下调。体外药敏试验表明，抑制miR-129-3p可使MDA-MB-231/Doc和MCF-7细胞对多西他赛敏感，而miR-129过表达则增强MDA-MB-231和MCF-7细胞对多西他赛的耐药性。在MDA-MB-231细胞中，异位表达miR-129可降低CP110表达以及基于CP110 3'非翻译区的报告基因构建体的荧光素酶活性，提示CP110是miR-129-3p的直接靶点。我们证明，在MDA-MB-231和MCF-7细胞中过表达miR-129来恢复CP110表达，可使细胞对多西他赛敏感。在裸鼠异种移植模型中，miR-129上调显著降低MDA-MB-231细胞对多西他赛的反应。我们的研究结果表明，下调miR-129-3p可能使乳腺癌细胞对多西他赛治疗敏感。
