miRNA-34a is associated with docetaxel resistance in human breast cancer cells
miRNA-34a is associated with docetaxel resistance in human breast cancer cells
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DOI：
10.1007/s10549-011-1424-3
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发表时间：
2012-01-01
影响因子：
3.8
通讯作者：
Schofield, A. C.
中科院分区：
文献类型：
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作者：
Kastl, L.;Brown, I.;Schofield, A. C.
多西紫杉醇是一种治疗乳腺癌的化疗药物，然而，与许多化疗药物一样，50%的患者对多西紫杉醇耐药，耐药的潜在分子机制尚不完全清楚。通过microRNAs （miRNA）进行的基因调控已被证明在癌症耐药中发挥重要作用。通过直接靶向mRNA， miRNAs能够抑制信号通路或药物诱导细胞凋亡所必需的基因，从而使细胞产生耐药性。本研究探讨了miRNA差异表达在两种体外乳腺癌细胞系模型（MCF-7、MDA-MB-231）获得性多西他赛耐药中的作用。MiRNA微阵列分析发现，在MCF-7和MDA-MB-231多西他赛耐药细胞中，分别有299和226个MiRNA发生改变。多西他赛耐药与miR-34a和miR-141的表达升高以及miR-7、miR-16、miR-30a、miR-125a-5p、miR-126的表达降低相关。计算靶标预测揭示了这些mirna靶向的8个候选基因。定量PCR和western分析证实，在多西他赛耐药细胞中，miR-34a靶向的两个基因BCL-2和CCND1的表达下降。miR-34a表达的调节与BCL-2和cyclin D1蛋白表达变化相关，荧光素酶测定显示miR-34a与BCL-2直接相互作用。抑制miR-34a可增强MCF-7多西紫杉醇耐药细胞对多西紫杉醇的应答，而过表达miR-34a可在MCF-7多西紫杉醇敏感细胞中产生耐药。本研究首次发现miRNA表达的差异，特别是在乳腺癌获得性多西他赛耐药模型中miR-34a的表达增加。这可能是这些细胞获得性多西他赛耐药的机制，可能通过与BCL-2和CCND1的直接相互作用，因此提供了治疗多西他赛耐药乳腺癌的潜在治疗靶点。
Docetaxel is a chemotherapy drug to treat breast cancer, however as with many chemotherapeutic drugs resistance to docetaxel occurs in 50% of patients, and the underlying molecular mechanisms of drug resistance are not fully understood. Gene regulation through microRNAs (miRNA) has been shown to play an important role in cancer drug resistance. By directly targeting mRNA, miRNAs are able to inhibit genes that are necessary for signalling pathways or drug induced apoptosis rendering cells drug resistant. This study investigated the role of differential miRNA expression in two in vitro breast cancer cell line models (MCF-7, MDA-MB-231) of acquired docetaxel resistance. MiRNA microarray analysis identified 299 and 226 miRNAs altered in MCF-7 and MDA-MB-231 docetaxel-resistant cells, respectively. Docetaxel resistance was associated with increased expression of miR-34a and miR-141 and decreased expression of miR-7, miR-16, miR-30a, miR-125a-5p, miR-126. Computational target prediction revealed eight candidate genes targeted by these miRNAs. Quantitative PCR and western analysis confirmed decreased expression of two genes, BCL-2 and CCND1, in docetaxel-resistant cells, which are both targeted by miR-34a. Modulation of miR-34a expression was correlated with BCL-2 and cyclin D1 protein expression changes and a direct interaction of miR-34a with BCL-2 was shown by luciferase assay. Inhibition of miR-34a enhanced response to docetaxel in MCF-7 docetaxel-resistant cells, whereas overexpression of miR-34a conferred resistance in MCF-7 docetaxel-sensitive cells. This study is the first to show differences in miRNA expression, in particular, increased expression of miR-34a in an acquired model of docetaxel resistance in breast cancer. This serves as a mechanism of acquired docetaxel resistance in these cells, possibly through direct interactions with BCL-2 and CCND1, therefore presenting a potential therapeutic target for the treatment of docetaxel-resistant breast cancer.