Construction of miRNA-miRNA networks revealing the complexity of miRNA-mediated mechanisms in trastuzumab treated breast cancer cell lines.
Construction of miRNA-miRNA networks revealing the complexity of miRNA-mediated mechanisms in trastuzumab treated breast cancer cell lines.
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DOI：
10.1371/journal.pone.0185558
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Gur Dedeoglu B
中科院分区：
文献类型：
--
作者：
Cilek EE;Ozturk H;Gur Dedeoglu B
曲妥珠单抗是一种单克隆抗体，常用于预防HER 2+乳腺癌的进展，占浸润性乳腺癌的约20%。microRNA（miRNAs）是已知参与基因调控的小的非编码RNA分子。随着它们在癌症中的新兴作用，它们最近被提升为通过靶向与药物反应相关的基因来介导治疗作用的潜在候选物。在这项研究中，我们通过同源网络分析确定了负责药物反应的重要miRNA，从而探索了miRNA介导的曲妥珠单抗调节机制。我们的网络模型使我们能够简化miRNA相互作用的复杂性，通过它们的共同途径将它们连接起来。我们分别在SKBR 3和BT474细胞中构建了基于通路的miRNA-miRNA网络，从而概述了功能相关的miRNAs。最靶向基因的鉴定显示，曲妥珠单抗应答性miRNA有利地调节具有比平均值更长的3 'UTR的靶标的抑制，这些靶标被认为是关键元件，而miRNA-miRNA网络突出了中心miRNA，如hsa-miR-3976和hsa-miR-3671，其显示出与网络的其余成员的强相互作用。此外，miRNA-miRNA网络的聚类显示曲妥珠单抗应答主要通过癌症相关和代谢途径建立。发现hsa-miR-216 b是代谢途径的最强大相互作用的一部分，其在两种细胞系中的最大簇中被定义。基于网络的miRNA-miRNA相互作用通过其共享途径的表示提供了对miRNA介导的药物反应的更好理解，并且可以建议用于进一步表征miRNA功能。
Trastuzumab is a monoclonal antibody frequently used to prevent the progression of HER2+ breast cancers, which constitute approximately 20% of invasive breast cancers. microRNAs (miRNAs) are small, non-coding RNA molecules that are known to be involved in gene regulation. With their emerging roles in cancer, they are recently promoted as potential candidates to mediate therapeutic actions by targeting genes associated with drug response. In this study we explored miRNA-mediated regulation of trastuzumab mechanisms by identifying the important miRNAs responsible for the drug response via homogenous network analysis. Our network model enabled us to simplify the complexity of miRNA interactions by connecting them through their common pathways. We outlined the functionally relevant miRNAs by constructing pathway-based miRNA-miRNA networks in SKBR3 and BT474 cells, respectively. Identification of the most targeted genes revealed that trastuzumab responsive miRNAs favourably regulate the repression of targets with longer 3’UTR than average considered to be key elements, while the miRNA-miRNA networks highlighted central miRNAs such as hsa-miR-3976 and hsa-miR-3671 that showed strong interactions with the remaining members of the network. Furthermore, the clusters of the miRNA-miRNA networks showed that trastuzumab response was mostly established through cancer related and metabolic pathways. hsa-miR-216b was found to be the part of the most powerful interactions of metabolic pathways, which was defined in the largest clusters in both cell lines. The network based representation of miRNA-miRNA interactions through their shared pathways provided a better understanding of miRNA-mediated drug response and could be suggested for further characterization of miRNA functions.
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影响因子：
64.8
作者：
Lu, J;Getz, G;Golub, TR
通讯作者：
Golub, TR
影响因子：
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通讯作者：
Bast RC Jr
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作者：
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