Park SM, Gaur AB, Lengyel E, Peter ME.. The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev 22: 894-907

The Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois 60637, USA.
Genes & Development (Impact Factor: 10.8). 05/2008; 22(7):894-907. DOI: 10.1101/gad.1640608
Source: PubMed


Cancer progression has similarities with the process of epithelial-to-mesenchymal transition (EMT) found during embryonic development, during which cells down-regulate E-cadherin and up-regulate Vimentin expression. By evaluating the expression of 207 microRNAs (miRNAs) in the 60 cell lines of the drug screening panel maintained by the Nation Cancer Institute, we identified the miR-200 miRNA family as an extraordinary marker for cells that express E-cadherin but lack expression of Vimentin. These findings were extended to primary ovarian cancer specimens. miR-200 was found to directly target the mRNA of the E-cadherin transcriptional repressors ZEB1 (TCF8/deltaEF1) and ZEB2 (SMAD-interacting protein 1 [SIP1]/ZFXH1B). Ectopic expression of miR-200 caused up-regulation of E-cadherin in cancer cell lines and reduced their motility. Conversely, inhibition of miR-200 reduced E-cadherin expression, increased expression of Vimentin, and induced EMT. Our data identify miR-200 as a powerful marker and determining factor of the epithelial phenotype of cancer cells.

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    • "Moreover numerous studies identified specific alterations in miRNAs signatures in different liver diseases. ZEB1 and ZEB2, the transcriptional repressors of E-cadherin are influenced by members of the miRNA-200 family and lead to epithelial to mesenchymal transition [125] [126]. Upregulation of miRNAs miR-200a and miR-200b in liver fibrosis is consistent with their influence in this disease mechanism [127]. "
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    ABSTRACT: Hepatocytes form a crucially important cell layer that separates sinusoidal blood from the canalicular bile. They have a uniquely organized polarity with a basal membrane facing liver sinusoidal endothelial cells, while one or more apical poles can contribute to several bile canaliculi jointly with the directly opposing hepatocytes. Establishment and maintenance of hepatocyte polarity is essential for many functions of hepatocytes and requires carefully orchestrated cooperation between cell adhesion molecules, cell junctions, cytoskeleton, extracellular matrix and intracellular trafficking machinery. The process of hepatocyte polarization requires energy and, if abnormal, may result in severe liver disease. A number of inherited disorders affecting tight junction and intracellular trafficking proteins have been described and demonstrate clinical and pathophysiological features overlapping those of the genetic cholestatic liver diseases caused by defects in canalicular ABC transporters. Thus both structural and functional components contribute to the final hepatocyte polarity phenotype. Many acquired liver diseases target factors that determine hepatocyte polarity, such as junctional proteins. Hepatocyte depolarization frequently occurs but is rarely recognized because hematoxylin-eosin staining does not identify the bile canaliculus. However, the molecular mechanisms underlying these defects are not well understood. Here we aim to provide an update on the key factors determining hepatocyte polarity and how it is affected in inherited and acquired diseases. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Jun 2015 · Journal of Hepatology
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    • "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]. This latter change is associated with more aggressive biological behavior in cancer, such as increased migration and invasion [20]. "
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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.
    Full-text · Article · May 2015 · Urologic Oncology
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    • "Epithelial-to-mesenchymal transition (EMT) is a phenomenon in which cells lose epithelial features and acquire MES characteristics leading to increased invasion and migration [24] [25]. Several transcription factors including SNAI1, SNAI2, TWIST1, ZEB-1 play important role in the MES differentiation [26] [27] and aberrant activation of transcriptional factors such as STAT3, ZEB-1and NFκB is shown to be responsible for MES shift in the GBM [12] [13] [28]. STAT3 is activated through phosphorylation of tyrosine 705 in response to cytokines and growth factors that results in transcription of diverse genes involved in cell cycle progression, apoptosis, cell survival, angiogenesis, migration, and invasion [29] [30] [31]. "
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    ABSTRACT: Glioblastoma (GBM), the most malignant of the brain tumors is classified on the basis of molecular signature genes using TCGA data into four subtypes- classical, mesenchymal, proneural and neural. The mesenchymal phenotype is associated with greater aggressiveness and low survival in contrast to GBMs enriched with proneural genes. The proinflammatory cytokines secreted in the microenvironment of gliomas play a key role in tumor progression. The study focused on the role of Oncostatin-M (OSM), an IL-6 family cytokine in inducing mesenchymal properties in GBM. Analysis of TCGA and REMBRANDT data revealed that expression of OSMR but not IL-6R or LIFR is upregulated in GBM and has negative correlation with survival. Amongst the GBM subtypes, OSMR level was in the order of mesenchymal > classical > neural > proneural. TCGA data and RT-PCR analysis in primary cultures of low and high grade gliomas showed a positive correlation between OSMR and mesenchymal signature genes-YKL40/CHI3L1, fibronectin and vimentin and a negative correlation with proneural signature genes-DLL3, Olig2 and BCAN. OSM enhanced transcript and protein level of fibronectin and YKL-40 and reduced the expression of Olig2 and DLL3 in GBM cells. OSM-regulated mesenchymal phenotype was associated with enhanced MMP-9 activity, increased cell migration and invasion. Importantly, OSM induced mesenchymal markers and reduced proneural genes even in primary cultures of grade-III glioma cells. We conclude that OSM-mediated signaling contributes to aggressive nature associated with mesenchymal features via STAT3 signaling in glioma cells. The data suggest that OSMR can be explored as potential target for therapeutic intervention. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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