microRNA 17/20 inhibits cellular invasion and tumor metastasis in breast cancer by heterotypic signaling

• Published in: Proceedings of the National Academy of Sciences - PNAS 2010-05, Vol.107 (18), p.8231-8236
• Main Authors: Yu, Zuoren, Willmarth, Nicole E, Zhou, Jie, Katiyar, Sanjay, Wang, Min, Liu, Yang, McCue, Peter A, Quong, Andrew A, Lisanti, Michael P, Pestell, Richard G
• Format: Article
• Language: English
• Subjects: 3' Untranslated Regions; Animals; Biological Sciences; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cell adhesion & migration; Cell cycle; Cell Line, Tumor; Cell lines; Cell Movement; Cyclins; Cytokines; Enzyme Activation; Gene expression regulation; Gene Expression Regulation, Neoplastic; Genes; Humans; Interleukin-8 - genetics; Interleukin-8 - metabolism; MicroRNA; MicroRNAs - genetics; Neoplasm Invasiveness; Neoplasm Metastasis; Plasminogen - metabolism; Plasminogen activators; Protein Binding; Ribonucleic acid; RNA; Secretion; Signal Transduction; Tissue samples; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1002080107

microRNAs are thought to regulate tumor progression and invasion via direct interaction with target genes within cells. Here the microRNA17/20 cluster is shown to govern cellular migration and invasion of nearby cells via heterotypic secreted signals. microRNA17/20 abundance is reduced in highly invasive breast cancer cell lines and node-positive breast cancer specimens. Cell-conditioned medium from microRNA17/20-overexpressing noninvasive breast cancer cell MCF7 was sufficient to inhibit MDA-MB-231 cell migration and invasion through inhibiting secretion of a subset of cytokines, and suppressing plasminogen activation via inhibition of the secreted plasminogen activators (cytokeratin 8 and α-enolase). microRNA17/20 directly repressed IL-8 by targeting its 3' UTR, and inhibited cytokeratin 8 via the cell cycle control protein cyclin D1. At variance with prior studies, these results demonstrated a unique mechanism of how the altered microRNA17/20 expression regulates cellular secretion and tumor microenvironment to control migration and invasion of neighboring cells in breast cancer. These findings not only reveal an antiinvasive function of miR-17/20 in breast cancer, but also identify a heterotypic secreted signal that mediates the microRNA regulation of tumor metastasis.