The miR-200 Family Inhibits Epithelial-Mesenchymal Transition and Cancer Cell Migration by Direct Targeting of E-cadherin Transcriptional Repressors ZEB1 and ZEB2

Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 06/2008; 283(22):14910-4. DOI: 10.1074/jbc.C800074200
Source: PubMed


MicroRNAs are small non-coding RNA molecules that can regulate gene expression by interacting with multiple mRNAs and inducing either translation suppression or degradation of mRNA. Recently, several miRNAs were identified as either promoters or suppressors of metastasis. However, it is unclear in which step(s) of the multistep metastatic cascade these miRNAs play a defined functional role. To study the functional importance of miRNAs in epithelial-mesenchymal transition (EMT), a process thought to initiate metastasis by enhancing the motility of tumor cells, we used a well established in vitro EMT assay: transforming growth factor-beta-induced EMT in NMuMG murine mammary epithelial cells. We found that members of the miR-200 family, organized as two clusters in the genome, were repressed during EMT. Overexpression of each miRNA individually or as clusters in NMuMG cells hindered EMT by enhancing E-cadherin expression through direct targeting of ZEB1 and ZEB2, which encode transcriptional repressors of E-cadherin. In the 4TO7 mouse carcinoma cell line, which expresses low levels of endogenous E-cadherin and displays a mesenchymal phenotype, ectopic expression of the miR-200 family miRNAs significantly increased E-cadherin expression and altered cell morphology to an epithelial phenotype. Furthermore, ectopic expression of each miR-200 miRNA cluster significantly reduced the in vitro motility of 4TO7 cells in migration assays. These results suggested that loss of expression of the miR-200 family members may play a critical role in the repression of E-cadherin by ZEB1 and ZEB2 during EMT, thereby enhancing migration and invasion during cancer progression.

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    • "In a recent study, miR-200c was shown to modulate EMT in human renal cell carcinoma [16]. ZEB1 and ZEB2 have been identified as direct targets of the miR-200 family in several cancer cells [17] [18], and down-regulation of ZEB1 and ZEB2 increases expression of E-cadherin. In contrast, loss of miR-200, which occurs in many human cancers, results in upregulation of ZEB1/ZEB2 and suppression of E-cadherin expression [18] [19]. "
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    ABSTRACT: MicroRNA-429 (miR-429), a short noncoding RNA belonging to the miR-200 superfamily, plays a crucial role in tumorigenesis and tumor progression. It also acts as a modulator of epithelial-to-mesenchymal transition, a cell development regulating process that affects tumor development and metastasis. The aim of this study was to investigate the potential role of miR-429 in regulating growth and metastasis of renal cell carcinoma. miR-429 expression was stably up-regulated or down-regulated in the renal cell carcinoma ACHN and A498 cell lines, and cell proliferation and metastasis were assessed. miR-429 overexpression inhibited cell proliferation, colony formation, migration, and invasion. Suppression of endogenous miR-429 promoted cell growth and metastasis. miR-429 was shown to directly target the 3' untranslated regions of B-cell-specific Moloney murine leukemia virus insertion site 1 (BMI1) and E2F transcription factor 3 (E2F3) transcripts, regulating their expression, as well as that of the downstream epithelial-to-mesenchymal transition markers E-cadherin, N-cadherin, vimentin, p14, and p16. These results revealed a tumor suppressive role for miR-429 in renal cell carcinoma through directly targeting BMI1 and E2F3. Copyright © 2015 Elsevier Inc. All rights reserved.
    Urologic Oncology 05/2015; 33(7). DOI:10.1016/j.urolonc.2015.03.016 · 2.77 Impact Factor
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    • "Snail factors can indeed promote the Wnt pathway (known for its regulation in selfrenewal and differentiation in stem cells) by E-Cad repression [62]. ZEB1 and ZEB2 factors downregulate some specific members of the microRNAs 200 family (miR-200), particularly miR-200c, which targets the polycomb group member BMI1, an essential regulator of stem-cell renewal, acting as a repressor of various genes by modulating the chromatin status [45] [63] [64]. More and more reports highlight the importance of the miR-200/ZEB feedback loop in determining epithelial and mesenchymal future of tumor cells [64]. "
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    ABSTRACT: Metastases are the hallmark of cancer. This event is in direct relationship with the ability of cancer cells to leave the tumor mass and travel long distances within the bloodstream and/or lymphatic vessels. Glioblastoma multiforme (GBM), the most frequent primary brain neoplasm, is mainly characterized by a dismal prognosis. The usual fatal issue for GBM patients is a consequence of local recurrence that is observed most of the time without any distant metastases. However, it has recently been documented that GBM cells could be isolated from the bloodstream in several studies. This observation raises the question of the possible involvement of glioblastoma-circulating cells in GBM deadly recurrence by a " homing metastasis " process. Therefore, we think it is important to review the already known molecular mechanisms underlying circulating tumor cells (CTC) specific properties, emphasizing their epithelial to mesenchymal transition (EMT) abilities and their possible involvement in tumor initiation. The idea is here to review these mechanisms and speculate on how relevant they could be applied in the forthcoming battles against GBM.
    Stem cell International 04/2015; 2015. DOI:10.1155/2015/182985 · 2.81 Impact Factor
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    • "The blocking of EMT and the activation of MET transition promote iPSC generation. mir-200 mediates suppression of Zeb1 and Zeb2 resulting in MET activation in early stage of reprogramming (Korpal et al., 2008; Wang et al., 2013b). mir-200 family is known to be regulated by c-Myc in an ESCspecific manner (Gill et al., 2011). "
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    ABSTRACT: Pluripotent stem cells (PSCs) have the capacity to differentiate into any cell type of the body. Therefore, induced pluripotent stem cells (iPSCs) are seen as promising solution for patient-specific cell therapies. However, the safety is major issue for in vitro methods, that are used in induction of pluripotency and also in differentiation of PSCs toward specific cell types. In pioneer studies of iPSC generation, the role of c-Myc has been highlighted as a possible master regulator of pluripotency, but direct c-Myc overexpression is known to prompt drawbacks, especially in human cells. In recent studies, the role of non-protein coding RNA molecules such as microRNAs (miRNAs) have been shown in enhanced reprogramming efficiency. In addition, new reprogramming methods have been ultimately improved by adding miRNAs, in the absence of previous factors. Cross interaction between miRNAs and c-Myc has been also found in differentiation of iPSCs, as well as in reprogramming and self-renewing the pluripotent state. Thence, miRNAs are promising solution for efficiency and safety of iPSC derivation and differentiation methods. The purpose of the present review is to evaluate interaction mechanisms of miRNAs with c-Myc and in iPSC technology. This article is protected by copyright. All rights reserved.
    Cell Biology International 03/2015; 39(9). DOI:10.1002/cbin.10467 · 1.93 Impact Factor
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