Division of Molecular Genome Analysis, German Cancer Research Center, Heidelberg, Germany.
Mol Syst Biol. 2012 Feb 14;8:570. doi: 10.1038/msb.2011.100.
The EGFR-driven cell-cycle pathway has been extensively studied due to its pivotal role in breast cancer proliferation and pathogenesis. Although several studies reported regulation of individual pathway components by microRNAs (miRNAs), little is known about how miRNAs coordinate the EGFR protein network on a global miRNA (miRNome) level. Here, we combined a large-scale miRNA screening approach with a high-throughput proteomic readout and network-based data analysis to identify which miRNAs are involved, and to uncover potential regulatory patterns. Our results indicated that the regulation of proteins by miRNAs is dominated by the nucleotide matching mechanism between seed sequences of the miRNAs and 3'-UTR of target genes. Furthermore, the novel network-analysis methodology we developed implied the existence of consistent intrinsic regulatory patterns where miRNAs simultaneously co-regulate several proteins acting in the same functional module. Finally, our approach led us to identify and validate three miRNAs (miR-124, miR-147 and miR-193a-3p) as novel tumor suppressors that co-target EGFR-driven cell-cycle network proteins and inhibit cell-cycle progression and proliferation in breast cancer.
由于 EGFR 驱动的细胞周期通路在乳腺癌增殖和发病机制中起着关键作用，因此已对其进行了广泛研究。尽管有几项研究报道了 microRNAs（miRNAs）对单个通路成分的调节，但对于 miRNAs 如何在全局 miRNA（miRNome）水平上协调 EGFR 蛋白网络知之甚少。在这里，我们结合了大规模的 miRNA 筛选方法和高通量蛋白质组学读数以及基于网络的数据分析，以确定哪些 miRNAs 参与其中，并揭示潜在的调控模式。我们的结果表明，miRNAs 对蛋白质的调节主要由 miRNA 的种子序列与靶基因 3'-UTR 之间的核苷酸匹配机制决定。此外，我们开发的新型网络分析方法暗示存在一致的内在调控模式，其中 miRNAs 同时共同调节几个在相同功能模块中起作用的蛋白质。最后，我们的方法使我们能够识别和验证三种 miRNA（miR-124、miR-147 和 miR-193a-3p）作为新型肿瘤抑制因子，它们共同靶向 EGFR 驱动的细胞周期网络蛋白，并抑制乳腺癌中的细胞周期进程和增殖。
