MicroRNAs as possible indicators of drug sensitivity in breast cancer cell lines
MicroRNAs as possible indicators of drug sensitivity in breast cancer cell lines
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DOI：
10.1371/journal.pone.0216400
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发表时间：
2019-05-07
期刊：
影响因子：
3.7
通讯作者：
Martens, John W. M.
中科院分区：
文献类型：
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作者：
Uhr, Katharina;Prager-van der Smissen, Wendy J. C.;Martens, John W. M.
MicroRNAs(MiRNAs)在转录后调节基因表达。通过这种方式，它们可能会影响细胞对某种药物的敏感性或抗药性。到目前为止，只进行了数量有限的相对较小规模的研究，包括很少的细胞系和/或药物。为了更广泛地了解miRNAs及其与药物反应的关系，我们调查了36个乳腺癌细胞系中411个miRNAs的表达水平与药物敏感性的关系。为此，涉及34种药物的药物筛选的IC50值与相同乳腺癌细胞系的miRNA表达数据相关联。由于乳腺癌细胞株的分子亚型在药物相关性研究中被认为是一个混杂因素，因此对保留了13个相关性的显著miRNA-药物相关性进行了考虑亚型的多变量分析。这些关联包括11种不同的miRNAs和8种不同的药物(其中包括紫杉醇、多西他赛和维利帕利)。紫杉醇和多西紫杉醇是唯一具有共同miRNAs的药物：hsa-miR-187-5p和hsa-miR-106a-3p指示耐药，而紫杉醇敏感性单独与hsa-miR-556-5p有关。维拉替尼对hsa-let-7d-5p和hsa-miR-18a-5p敏感，对hsa-miR-637耐药。药物敏感性与hsa-let-7a-5p对Bortezomib、hsa-miR-135a-3p对JNJ-707和hsa-miR-185-3p对Panobinostat有关。Veliparib的耐药性与hsa-miR-182-5p有关，替法尼布的耐药性与hsa-miR-629-5p有关。对重要的miRNAs进行了通路分析，以揭示生物学作用，帮助找到所观察到的与药物反应相关的潜在机制联系。通过这样做，hsa-miR-187-5p被连接到细胞周期G2-M检查点，该检查点是紫杉烷的靶标。总之，我们的研究表明miRNAs可能作为内在耐药性的生物标记物，而通路分析可以在这方面提供更多的信息。
MicroRNAs (miRNAs) regulate gene expression post-transcriptionally. In this way they might influence whether a cell is sensitive or resistant to a certain drug. So far, only a limited number of relatively small scale studies comprising few cell lines and/or drugs have been performed. To obtain a broader view on miRNAs and their association with drug response, we investigated the expression levels of 411 miRNAs in relation to drug sensitivity in 36 breast cancer cell lines. For this purpose IC50 values of a drug screen involving 34 drugs were associated with miRNA expression data of the same breast cancer cell lines. Since molecular subtype of the breast cancer cell lines is considered a confounding factor in drug association studies, multivariate analysis taking subtype into account was performed on significant miRNA-drug associations which retained 13 associations. These associations consisted of 11 different miRNAs and eight different drugs (among which Paclitaxel, Docetaxel and Veliparib). The taxanes, Paclitaxel and Docetaxel, were the only drugs having miRNAs in common: hsa-miR-187-5p and hsa-miR-106a-3p indicative of drug resistance while Paclitaxel sensitivity alone associated with hsa-miR-556-5p. Tivantinib was associated with hsa-let-7d-5p and hsa-miR-18a-5p for sensitivity and hsa-miR-637 for resistance. Drug sensitivity was associated with hsa-let-7a-5p for Bortezomib, hsa-miR-135a-3p for JNJ-707 and hsa-miR-185-3p for Panobinostat. Drug resistance was associated with hsa-miR-182-5p for Veliparib and hsa-miR-629-5p for Tipifarnib. Pathway analysis for significant miRNAs was performed to reveal biological roles, aiding to find a potential mechanistic link for the observed associations with drug response. By doing so hsa-miR-187-5p was linked to the cell cycle G2-M checkpoint in line with this checkpoint being the target of taxanes. In conclusion, our study shows that miRNAs could potentially serve as biomarkers for intrinsic drug resistance and that pathway analyses can provide additional information in this context.