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    Keywords: EXPRESSION ; LINES ; DYNAMICS ; breast cancer ; REQUIRES ; SERUM RESPONSE FACTOR ; EPITHELIAL-MESENCHYMAL TRANSITION ; miR-200 family ; FORMIN ; FIBER FORMATION ; ZEB1
    Abstract: MicroRNA-200c (miR-200c) has been shown to suppress epithelial-to-mesenchymal transition (EMT), which is mainly attributed to targeting of ZEB1/ZEB2, repressors of the cell-cell contact protein E-Cadherin. Here, we demonstrated that modulation of miR-200c in breast cancer cells regulates cell migration, cell elongation and TGF-beta-induced stress fiber formation, by impacting the re-organization of cytoskeleton that is independent of the ZEB/E-Cadherin-axis. We identified FHOD1 and PPM1F, direct regulators of the actin cytoskeleton, as novel targets of miR-200c. Remarkably, expression levels of FHOD1 and PPM1F were inversely correlated with miR-200c in breast cancer cell lines, breast cancer patient samples, as well as in 58 cancer cell lines of various origin. Furthermore, individual knockdown/overexpression of these target genes phenocopied the effects of miR-200c overexpression/inhibition on cell elongation, stress fiber formation, migration and invasion. Mechanistically, targeting of FHOD1 by miR-200c resulted in decreased expression and transcriptional activity of SRF mediated by interference with the translocation of SRF co-activator MRTF-A. This finally led to downregulation of the expression and phosphorylation of the SRF target gene MLC2 required for stress fiber formation and contractility. Thus, miR-200c impacts on metastasis by regulating several EMT-related processes, including a novel mechanism involving the direct targeting of actin-regulatory proteins.
    Type of Publication: Journal article published
    PubMed ID: 22144583
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