A global microRNA screen identifies regulators of the ErbB receptor signaling network.
A global microRNA screen identifies regulators of the ErbB receptor signaling network.
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DOI：
10.1186/s12964-015-0084-z
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发表时间：
2015-01-29
期刊：
影响因子：
--
通讯作者：
Olayioye MA
中科院分区：
文献类型：
--
作者：
Bischoff A;Bayerlová M;Strotbek M;Schmid S;Beissbarth T;Olayioye MA
生长因子Hereglin(HRG)通过与其同源受体ErbB3(也称为HER3)结合，有效地刺激上皮细胞的存活和增殖。ErbB3依赖的信号传递依赖于二聚化伙伴ErbB2，这是一种受体酪氨酸激酶，在乳腺癌细胞中经常过度表达和/或放大。大量证据表明，解除调控的ErbB3表达也有助于乳腺癌细胞的转化表型。通过全基因组筛选，我们鉴定出43个microRNAs(MiRNAs)，它们特异性地影响HRG诱导的PI3K-Akt途径的激活。生物信息学分析与实验验证相结合，揭示了一个高度连接的分子miRNA-基因相互作用网络，特别是对于阴性筛选命中。对于选定的miRNAs，即miR-149、miR-148B、miR-326和miR-520a-3p，我们证明了ErbB3受体和多个下游信号分子的同时下调，解释了它们有效地抑制HRG反应，并将其归因于这些miRNAs潜在的上下文相关的肿瘤抑制功能。鉴于HRG信号尤其是PI3K-Akt通路在肿瘤发生中的作用，本研究不仅提供了对miRNAs功能的机械性见解，而且对未来的临床应用也有一定的意义。本文的在线版本(doi：10.1186/s12964-0150084-z)包含补充材料，授权用户可以使用。
The growth factor heregulin (HRG) potently stimulates epithelial cell survival and proliferation through the binding of its cognate receptor ErbB3 (also known as HER3). ErbB3-dependent signal transmission relies on the dimerization partner ErbB2, a receptor tyrosine kinase that is frequently overexpressed and/or amplified in breast cancer cells. Substantial evidence suggests that deregulated ErbB3 expression also contributes to the transformed phenotype of breast cancer cells. By genome-wide screening, we identify 43 microRNAs (miRNAs) that specifically impact HRG-induced activation of the PI3K-Akt pathway. Bioinformatic analysis combined with experimental validation reveals a highly connected molecular miRNA-gene interaction network particularly for the negative screen hits. For selected miRNAs, namely miR-149, miR-148b, miR-326, and miR-520a-3p, we demonstrate the simultaneous downregulation of the ErbB3 receptor and multiple downstream signaling molecules, explaining their efficient dampening of HRG responses and ascribing to these miRNAs potential context-dependent tumor suppressive functions. Given the contribution of HRG signaling and the PI3K-Akt pathway in particular to tumorigenesis, this study not only provides mechanistic insight into the function of miRNAs but also has implications for future clinical applications. The online version of this article (doi:10.1186/s12964-015-0084-z) contains supplementary material, which is available to authorized users.
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