Decreased expression of microRNA-17 and microRNA-20b promotes breast cancer resistance to taxol therapy by upregulation of NCOA3.
Decreased expression of microRNA-17 and microRNA-20b promotes breast cancer resistance to taxol therapy by upregulation of NCOA3.
复制标题
microRNA-17 和 microRNA-20b 表达的减少通过上调 NCOA3 促进乳腺癌对紫杉醇治疗的耐药性。
DOI：
10.1038/cddis.2016.367
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发表时间：
2016-11-10
影响因子：
9
通讯作者：
Zou Z
中科院分区：
文献类型：
--
作者：
Ao X;Nie P;Wu B;Xu W;Zhang T;Wang S;Chang H;Zou Z
化疗耐药性是乳腺癌有效化疗的主要障碍。然而，潜在的分子机制仍不清楚。在这项研究中，发现核受体辅激活因子3（NCOA 3）在紫杉醇耐药的乳腺癌组织和细胞中显着增加。此外，NCOA 3的过表达增强了乳腺癌细胞对紫杉醇的耐药性，而NCOA 3的缺失降低了紫杉醇耐药性。随后，我们研究了乳腺癌中NCOA 3的表达是否受到miRNA的调控。通过生物信息学预测，结合前期报道的数据，筛选出miR-17和miR-20 b作为靶向NCOA 3的潜在miRNAs。通过实时荧光定量PCR分析，我们发现miR-17和miR-20 b在紫杉醇耐药的乳腺癌组织和细胞中显著减少。此外，我们还提供了miR-17和miR-20 b在体外和体内模型中减弱乳腺癌对紫杉醇耐药性的实验证据。此外，通过荧光素酶报告基因分析，我们进一步证实了miR-17和miR-20 b均直接与乳腺癌细胞中NCOA 3 mRNA的3′-非翻译区结合，并抑制其表达。最后，发现miR-17和miR-20 b水平均与乳腺癌组织中的NCOA 3 mRNA水平显著负相关。总之，我们的研究结果表明，miR-17和miR-20 b的缺失通过上调NCOA 3水平增强了乳腺癌对紫杉醇的耐药性。我们的研究提示miR-17、miR-20 b和NCOA 3可能作为紫杉醇耐药乳腺癌治疗的预测性生物标志物和潜在的治疗靶点。
Chemoresistance is a major obstacle to effective breast cancer chemotherapy. However, the underlying molecular mechanisms remain unclear. In this study, nuclear receptor coactivator 3 (NCOA3) was found to be significantly increased in taxol-resistant breast cancer tissues and cells. Moreover, overexpression of NCOA3 enhanced breast cancer cell resistance to taxol, whereas depletion of NCOA3 decreased taxol resistance. Subsequently, we investigated whether NCOA3 expression was regulated by miRNAs in breast cancer. By bioinformatics prediction in combination with the data of previous report, miR-17 and miR-20b were selected as the potential miRNAs targeting NCOA3. By real-time PCR analysis, we found that miR-17 and miR-20b were significantly reduced in taxol-resistant breast cancer tissues and cells. In addition, we provided some experimental evidences that miR-17 and miR-20b attenuated breast cancer resistance to taxol in vitro and in vivo models. Furthermore, by luciferase reporter assays, we further validated that both miR-17 and miR-20b directly binded the 3′-untranslated region of NCOA3 mRNA and inhibited its expression in breast cancer cells. Finally, both miR-17 and miR-20b levels were found to be significantly negatively correlated with NCOA3 mRNA levels in breast cancer tissues. Together, our results indicated that loss of miR-17 and miR-20b enhanced breast cancer resistance to taxol by upregulating NCOA3 levels. Our study suggested miR-17, miR-20b and NCOA3 may serve as some predictive biomarkers and potential therapeutic targets in taxol-resistant breast cancer treatment.