期刊
MOLECULAR SYSTEMS BIOLOGY
卷 8, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/msb.2011.100
关键词
breast cancer; EGFR signaling; microRNA; miRNA-protein interaction network; network analysis
资金
- National Genome Research Network [01GS0864]
- Medical Systems Biology program [0315396B]
- German Federal Ministry of Education and Research (BMBF)
- Wilhelm Sanderstiftung [2009.051.1]
- DKFZ
- Heidelberg Graduate School of Mathematical and Computational Methods for the Sciences, University of Heidelberg, Germany
- German Excellence Initiative [GSC 220]
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 30-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.
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