Targeting the miR-200c/LIN28B axis in acquired EGFR-TKI resistance non-small cell lung cancer cells harboring EMT features.
Targeting the miR-200c/LIN28B axis in acquired EGFR-TKI resistance non-small cell lung cancer cells harboring EMT features.
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DOI：
10.1038/srep40847
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发表时间：
2017-01-13
影响因子：
4.6
通讯作者：
Toyooka S
中科院分区：
文献类型：
--
作者：
Sato H;Shien K;Tomida S;Okayasu K;Suzawa K;Hashida S;Torigoe H;Watanabe M;Yamamoto H;Soh J;Asano H;Tsukuda K;Miyoshi S;Toyooka S
microRNA（miR）-200家族成员（miR-200 s）在晚期癌症中经常沉默，并参与上皮向间充质转化（EMT）的过程。我们以前报道过，miR-200通过启动子甲基化在获得性EGFR-酪氨酸激酶抑制剂（TKI）耐药的非小细胞肺癌（NSCLC）细胞中沉默，这些细胞具有EMT特征。在这项研究中，我们研究了miR-200在NSCLC细胞中的功能作用，并研究了克服获得性EGFR-TKI耐药性的新方法。在NSCLC细胞系的分析中，每种miR-200表达沉默的细胞系均显示启动子甲基化。在数据库分析中观察到miR-200 c沉默与几种致癌途径改变（包括EMT变化和LIN 28 B过表达）之间的显著相关性。此外，EGFR野生型细胞系的miR-200表达水平低于EGFR突变型细胞系。使用pre-miR-200 c引入miR-200 c在具有获得性EGFR-TKI抗性的细胞中引起LIN 28 B抑制，所述获得性EGFR-TKI抗性具有EMT特征。有趣的是，miR-200 c的引入和LIN 28 B的敲低在获得性EGFR-TKI抗性细胞中产生抗肿瘤作用，而这些操作在亲本细胞中无效。miR-200 c/LIN 28 B轴在具有对EGFR-TKI的获得性耐药的细胞中起重要作用，所述细胞具有EMT特征，并且可能是克服耐药的有用的治疗靶标。
MicroRNA (miR)-200 family members (miR-200s) are frequently silenced in advanced cancer and have been implicated in the process of epithelial-to-mesenchymal transition (EMT). We previously reported that miR-200s were silenced through promoter methylation in acquired EGFR-tyrosine kinase inhibitor (TKI) resistant non-small cell lung cancer (NSCLC) cells harboring EMT features. In this study, we examined the functional role of miR-200s in NSCLC cells and investigated a novel approach to overcoming acquired EGFR-TKI resistance. In the analysis of NSCLC cell lines, each of the miR-200s expression-silenced cell lines showed promoter methylation. Significant correlations between miR-200c silencing and several oncogenic pathway alterations, including EMT-changes and LIN28B overexpression, were observed in the database analysis. In addition, EGFR-wild type cell lines had lower miR-200s expression levels than EGFR-mutant cell lines. The introduction of miR-200c using pre-miR-200c caused LIN28B suppression in cells with acquired EGFR-TKI resistance that harbored EMT features. Interestingly, both the introduction of miR-200c and the knockdown of LIN28B produced an antitumor effect in acquired EGFR-TKI resistance cells, whereas these manipulations were not effective in parental cells. The miR-200c/LIN28B axis plays an important role in cells with acquired resistance to EGFR-TKI that harbor EMT features and might be a useful therapeutic target for overcoming resistance.