Bischoff Annabell, Bayerlová Michaela, Strotbek Michaela, Schmid Simone, Beissbarth Tim, Olayioye Monilola A
Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, Stuttgart, 70569, Germany.
Cell Commun Signal. 2015 Jan 29;13:5. doi: 10.1186/s12964-015-0084-z.
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.
生长因子神经调节蛋白（HRG）通过与其同源受体ErbB3（也称为HER3）结合，有力地刺激上皮细胞存活和增殖。依赖ErbB3的信号转导依赖于二聚化伴侣ErbB2，后者是一种受体酪氨酸激酶，在乳腺癌细胞中经常过度表达和/或扩增。大量证据表明，失调的ErbB3表达也促成了乳腺癌细胞的转化表型。
通过全基因组筛选，我们鉴定出43种特异性影响HRG诱导的PI3K-Akt途径激活的微小RNA（miRNA）。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的情况。对于选定的miRNA，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同时下调，解释了它们对HRG反应的有效抑制，并将这些miRNA的潜在上下文依赖性肿瘤抑制功能归因于此。
鉴于HRG信号传导，特别是PI3K-Akt途径对肿瘤发生的作用，本研究不仅提供了对miRNA功能的机制性见解，而且对未来的临床应用也有影响。
