Re-expression of microRNA-375 reverses both tamoxifen resistance and accompanying EMT-like properties in breast cancer
Re-expression of microRNA-375 reverses both tamoxifen resistance and accompanying EMT-like properties in breast cancer
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DOI：
10.1038/onc.2012.128
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发表时间：
2013-02-28
期刊：
影响因子：
8
通讯作者：
Sahin, Oe
中科院分区：
文献类型：
--
作者：
Ward, A.;Balwierz, A.;Sahin, Oe
上皮-间质转化（epithelial-meschynnal transition，EMT）是肿瘤细胞侵袭和转移的起始事件。它已被证明发生在对一系列癌症治疗的耐药性中，包括他莫昔芬。microRNA（miRNAs）与EMT以及对标准疗法的抗性相关。为了研究nniRNA在他莫昔芬耐药性发展中的作用以及伴随的EMT样性质，我们通过持续将MCF-7乳腺癌细胞暴露于他莫昔芬来建立他莫昔芬耐药（TamR）模型。除了已知参与获得性他莫昔芬耐药的分子变化外，TamR细胞还显示了间质特征，并具有增加的侵袭性。全基因组miRNA微阵列分析显示，miRNA-375是耐药细胞中下调最多的miRNA之一。miR-375的再表达足以使TamR细胞对他莫昔芬敏感并部分逆转EMT。mRNA谱分析、生物信息学分析和实验验证的组合将metadherin（MTDH）鉴定为miR-375的直接靶标。MTDH的敲除部分表型模拟了miR-375对他莫昔芬敏感性和EMT逆转的作用。我们在原发性乳腺癌样本中观察到miR-375的表达与其靶向MTDH之间的负相关性，这意味着靶向的病理相关性。最后，MTDH表达较高的他莫昔芬治疗患者的无病生存期较短，复发风险较高。由于大多数癌症相关死亡是由于对标准疗法的抗性和转移而发生的，因此miR-375的再表达或靶向MTDH可能作为治疗TamR乳腺癌的潜在治疗方法。Oncogene（2013）32，1173-1182; doi：10.1038/onc.2012.128; 2012年4月16日在线发表
Epithelial-mesenchynnal transition (EMT) is an initiating event in tumor cell invasion and metastasis. It has been shown to occur in resistance to a range of cancer therapies, including tamoxifen. MicroRNAs (miRNAs) have been associated with EMT as well as resistance to standard therapies. To investigate the role of nniRNAs in the development of resistance to tamoxifen as well as accompanying EMT-like properties, we established a tamoxifen-resistant (TamR) model by continually exposing MCF-7 breast cancer cells to tamoxifen. In addition to the molecular changes known to be involved in acquired tamoxifen resistance, TamR cells displayed nnesenchymal features and had increased invasiveness. Genome-wide miRNA microarray analysis revealed that miRNA-375 was among the top downregulated miRNAs in resistant cells. Re-expression of miR-375 was sufficient to sensitize TamR cells to tamoxifen and partly reversed EMT. A combination of mRNA profiling, bioinformatics analysis and experimental validation identified metadherin (MTDH) as a direct target of miR-375. Knockdown of MTDH partially phenocopied the effects of miR-375 on the sensitivity to tamoxifen and the reversal of EMT. We observed an inverse correlation between the expression of miR-375 and its target MTDH in primary breast cancer samples, implying the pathological relevance of targeting. Finally, tamoxifen-treated patients with higher expression of MTDH had a shorter disease-free survival and higher risk of relapse. As most cancer-related deaths occur because of resistance to standard therapies and metastasis, re-expression of miR-375 or targeting MTDH might serve as potential therapeutic approaches for the treatment of TamR breast cancer. Oncogene (2013) 32, 1173-1182; doi:10.1038/onc.2012.128; published online 16 April 2012