title: microRNA 17/20 inhibits cellular invasion and tumor metastasis in breast cancer by heterotypic signaling.
abstract: 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 alpha-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.
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University and Hospital, Kimmel Cancer Center, Philadelphia, PA 19107, USA.
authors.forename: Zuoren
authors.initials: Z
authors.lastname: Yu
authors.forename: Nicole E
authors.initials: NE
authors.lastname: Willmarth
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.forename: Sanjay
authors.initials: S
authors.lastname: Katiyar
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Peter A
authors.initials: PA
authors.lastname: McCue
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Quong
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010958:Plasminogen / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction
chemical_list: D020413:3' Untranslated Regions; D016209:Interleukin-8; C524941:MIRN17 microRNA, human; C534451:MIRN20a microRNA, human; D035683:MicroRNAs; D010958:Plasminogen
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