The emerging role of miR-200 family of MicroRNAs in epithelial-mesenchymal transition and cancer metastasis

Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA.
RNA biology (Impact Factor: 5.38). 08/2008; 5(3):115-9. DOI: 10.4161/rna.5.3.6558
Source: PubMed

ABSTRACT MicroRNAs (miRNAs) play essential roles in many physiological and pathological processes, including tumor development, by regulating the expression of a plethora of mRNAs. Although the importance of miRNAs in tumorigenesis is well established, only recently have reports elucidated miRNAs as promoters or suppressors of metastasis. The miR-200 family has been shown to inhibit the initiating step of metastasis, epithelial-mesenchymal transition (EMT), by maintaining the epithelial phenotype through direct targeting of transcriptional repressors of E-cadherin, ZEB1 and ZEB2. These findings shed light into a miRNA-mediated regulatory pathway that influences EMT in a developmentally and pathologically relevant setting.

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    • "In our result, mir-200a, mir-200b and mir-429 were all up-regulated, which indicates the important role of the miR-200 family in podocyte differentiation. In fact, series researchers have reported the pivotal role of miR-200 family in development and disease (Choi et al. 2008; Korpal and Kang 2008). To our surprise, mir-200a, mir-200b and mir-429 were all involved in the regulated microRNAs that were potentially regulated by the three transcription factors P53, SP1 and CREB (Table 1). "
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    ABSTRACT: The podocyte is a prominent cell type, which encases the capillaries of glomerulus. Podocyte-selective deletion of Dicer or Drosha was reported to induce proteinuria and glomerulosclerosis, suggesting the essential role of microRNA (miRNA) in podocytes for renal function. However, no comprehensive miRNA expression or miRNA-mRNA integrated analysis (MMIA) can be found during podocyte differentiation. Herein, miRNA and mRNA microarrays are presented, which were carried out in differentiated and undifferentiated mouse podocyte cell lines (MPC5). A total of 50 abnormal miRNAs (26 down-regulated and 24 up-regulated) were identified in differentiated and undifferentiated podocytes. Using MMIA, 80 of the 743 mRNAs (>twofold change) were predicted for potential crosstalk with 30 miRNAs of the 50 abnormal miRNAs. In addition, the gene ontology of mRNAs and the pathway analysis of miRNAs revealed a new potential-regulated network during podocyte differentiation. The expressions of three remarkably changed miRNAs (miR-34c, miR-200a and miR-467e) and four mRNAs (Runx1t1, Atp2a2, Glrp1, and Mmp15), were randomly chosen for further validation by the quantitative real-time polymerase chain reaction, and their expression trends were consistent with the microarray data. Reference searching was also conducted to confirm our data and to find potential new molecules and miRNA-target pairs involved in the podocyte differentiation. The dual luciferase reporter assay for miR-200a/GLRX and let-7b/ARL4D confirmed the prediction of MMIA. The results of this study provide a detailed integration of mRNA and miRNA during podocyte differentiation. The molecular integration mode will open up new perspectives for a better understanding of the mechanism during podocyte differentiation.
    Molecular Genetics and Genomics 11/2014; 290(3). DOI:10.1007/s00438-014-0960-z · 2.83 Impact Factor
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    • "Patients with tumours that express these receptors often have a better prognosis because they respond well to treatments such as Tamoxifen. We hypothesize that methylation at P2, is likely to be associated with a lower level of miRNA expression, resulting in a more aggressive tumour (Korpal and Kang, 2008) that is unresponsive to these therapies and generally associated with poor prognosis. Using publicly available ER Chip-sequence data (Schmidt et al., 2010), ER bound to a putative ER response element just downstream of P1 upon ER stimulation in MCF7s (Figure 6e). "
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    ABSTRACT: MicroRNAs (miRNAs) are small non-coding RNAs of ∼20 nt in length that are capable of modulating gene expression post-transcriptionally. Although miRNAs have been implicated in cancer, including breast cancer, the regulation of miRNA transcription and the role of defects in this process in cancer is not well understood. In this study we have mapped the promoters of 93 breast cancer-associated miRNAs, and then looked for associations between DNA methylation of 15 of these promoters and miRNA expression in breast cancer cells. The miRNA promoters with clearest association between DNA methylation and expression included a previously described and a novel promoter of the Hsa-mir-200b cluster. The novel promoter of the Hsa-mir-200b cluster, denoted P2, is located ∼2 kb upstream of the 5' stemloop and maps within a CpG island. P2 has comparable promoter activity to the previously reported promoter (P1), and is able to drive the expression of miR-200b in its endogenous genomic context. DNA methylation of both P1 and P2 was inversely associated with miR-200b expression in eight out of nine breast cancer cell lines, and in vitro methylation of both promoters repressed their activity in reporter assays. In clinical samples, P1 and P2 were differentially methylated with methylation inversely associated with miR-200b expression. P1 was hypermethylated in metastatic lymph nodes compared with matched primary breast tumours whereas P2 hypermethylation was associated with loss of either oestrogen receptor or progesterone receptor. Hypomethylation of P2 was associated with gain of HER2 and androgen receptor expression. These data suggest an association between miR-200b regulation and breast cancer subtype and a potential use of DNA methylation of miRNA promoters as a component of a suite of breast cancer biomarkers.
    Oncogene 01/2012; 31(38):4182-95. DOI:10.1038/onc.2011.584 · 8.56 Impact Factor
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    • "In addition, a recent report showed that gemcitabine sensitivity can be induced in pancreatic cancer cells through modulation of miR-200 and miR-21 expression by curcumin (Ali et al. 2010). The miR-200 family has been shown to inhibit the EMT, the initiating step of metastasis, by maintaining the epithelial phenotype through direct targeting of the transcriptional repressors of E-cadherin, ZEB1, and ZEB2 (Korpal and Kang 2008). Therefore, targeting specific miRNAs could be a novel therapeutic approach for the treatment of cancers, especially by eliminating cancer stem cells or EMT-type cells that are typically drug resistant. "
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    ABSTRACT: Epigenetic regulation, which includes changes in DNA methylation, histone modifications, and alteration in microRNA (miRNA) expression without any change in the DNA sequence, constitutes an important mechanism by which dietary components can selectively activate or inactivate gene expression. Curcumin (diferuloylmethane), a component of the golden spice Curcuma longa, commonly known as turmeric, has recently been determined to induce epigenetic changes. This review summarizes current knowledge about the effect of curcumin on the regulation of histone deacetylases, histone acetyltransferases, DNA methyltransferase I, and miRNAs. How these changes lead to modulation of gene expression is also discussed. We also discuss other nutraceuticals which exhibit similar properties. The development of curcumin for clinical use as a regulator of epigenetic changes, however, needs further investigation to determine novel and effective chemopreventive strategies, either alone or in combination with other anticancer agents, for improving cancer treatment.
    Genes & Nutrition 05/2011; 6(2):93-108. DOI:10.1007/s12263-011-0222-1 · 3.42 Impact Factor
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