Article

MicroRNA-200c represses migration and invasion of breast cancer cells by targeting actin-regulatory proteins FHOD1 and PPM1F

Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Molecular and Cellular Biology (Impact Factor: 5.04). 12/2011; 32(3):633-51. DOI: 10.1128/MCB.06212-11
Source: PubMed

ABSTRACT MicroRNA-200c (miR-200c) has been shown to suppress epithelial-mesenchymal transition (EMT), which is attributed mainly 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 transforming growth factor β (TGF-β)-induced stress fiber formation by impacting the reorganization 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 the level of miR-200c in breast cancer cell lines, breast cancer patient samples, and 58 cancer cell lines of various origins. 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 serum response factor (SRF), mediated by interference with the translocation of the SRF coactivator mycocardin-related transcription factor A (MRTF-A). This finally led to downregulation of the expression and phosphorylation of the SRF target myosin light chain 2 (MLC2) gene, 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.

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    • "We identified 117 novel metastasis-related miRNAs in NSCLC based on a well-established metastasis cell model [19]. The finding that miR-200c was downregulated in metastatic SPC-A-1sci cells was intriguing, because decreased miR-200c levels have been reported in several other types of tumor [21,23-25], thus indicating that decreased miR-200c may be a common event in the tumorigenesis. Other reports showed serum miR-200c associated with poor prognosis in patients with lung cancer [32]. "
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    • "We observed an inverse correlation between miR-200c expression and expression of MUC1, and further evaluated the regulation behind this correlation. MiR-200c regulates a number of proteins associated with epithelial cell differentiation and processes associated with progression of adenocarcinomas [8–11]. Given that MUC1 is known to regulate transcription of a number of processes associated with tumor progression, we hypothesized that transcription of miR-200c was regulated by signal transduction through MUC1. "
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    PLoS ONE 10/2013; 8(10):e73306. DOI:10.1371/journal.pone.0073306 · 3.23 Impact Factor
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    • "ZEB1 inhibits miR-200c expression, while miR-200c in turn inhibits EMT by targeting ZEB1 thereby creating a negative feedback loop [66]. In breast cancer, miR-200c has also been reported to repress EMT independently of ZEB1, by silencing FHOD1, and PPM1F (both play a key role in remodelling the actin cytoskeleton from an epithelial to a mesenchymal phenotype) [67]. This further suggests that enhancing miR-200c expression could be a viable option to limit metastases. "
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