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      miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis

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          Abstract

          MicroRNAs (miRNAs) are increasingly implicated in regulating the malignant progression of cancer. Here we show that miR-9, the level of which is upregulated in breast cancer cells, directly targets CDH1, the E-cadherin-encoding mRNA, leading to increased cell motility and invasiveness. miR-9-mediated E-cadherin downregulation results in the activation of β-catenin signaling, which contributes to upregulated expression of the gene encoding vascular endothelial growth factor (VEGF); this leads, in turn, to increased tumor angiogenesis. Overexpression of miR-9 in otherwise-non-metastatic breast tumor cells enables these cells to form pulmonary micrometastases in mice. Conversely, inhibiting miR-9 using a ‘miRNA sponge’ in highly malignant cells inhibits metastasis formation. Expression of miR-9 is activated by MYC and MYCN, both of which directly bind to the mir-9-3 locus. Significantly, in human cancers, miR-9 levels correlate with MYCN amplification, tumor grade, and metastatic status. These findings uncover a regulatory and signaling pathway involving a metastasis-promoting miRNA that is predicted to directly target expression of the key metastasis-suppressing protein E-cadherin.

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          Most cited references29

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          Connecting microRNA genes to the core transcriptional regulatory circuitry of embryonic stem cells.

          MicroRNAs (miRNAs) are crucial for normal embryonic stem (ES) cell self-renewal and cellular differentiation, but how miRNA gene expression is controlled by the key transcriptional regulators of ES cells has not been established. We describe here the transcriptional regulatory circuitry of ES cells that incorporates protein-coding and miRNA genes based on high-resolution ChIP-seq data, systematic identification of miRNA promoters, and quantitative sequencing of short transcripts in multiple cell types. We find that the key ES cell transcription factors are associated with promoters for miRNAs that are preferentially expressed in ES cells and with promoters for a set of silent miRNA genes. This silent set of miRNA genes is co-occupied by Polycomb group proteins in ES cells and shows tissue-specific expression in differentiated cells. These data reveal how key ES cell transcription factors promote the ES cell miRNA expression program and integrate miRNAs into the regulatory circuitry controlling ES cell identity.
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            Widespread microRNA repression by Myc contributes to tumorigenesis.

            The c-Myc oncogenic transcription factor (Myc) is pathologically activated in many human malignancies. Myc is known to directly upregulate a pro-tumorigenic group of microRNAs (miRNAs) known as the miR-17-92 cluster. Through the analysis of human and mouse models of B cell lymphoma, we show here that Myc regulates a much broader set of miRNAs than previously anticipated. Unexpectedly, the predominant consequence of activation of Myc is widespread repression of miRNA expression. Chromatin immunoprecipitation reveals that much of this repression is likely to be a direct result of Myc binding to miRNA promoters. We further show that enforced expression of repressed miRNAs diminishes the tumorigenic potential of lymphoma cells. These results demonstrate that extensive reprogramming of the miRNA transcriptome by Myc contributes to tumorigenesis.
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              • Record: found
              • Abstract: found
              • Article: not found

              Regulation of cadherin-mediated adhesion in morphogenesis.

              Cadherin cell-adhesion proteins mediate many facets of tissue morphogenesis. The dynamic regulation of cadherins in response to various extracellular signals controls cell sorting, cell rearrangements and cell movements. Cadherins are regulated at the cell surface by an inside-out signalling mechanism that is analogous to the integrins in platelets and leukocytes. Signal-transduction pathways impinge on the catenins (cytoplasmic cadherin-associated proteins), which transduce changes across the membrane to alter the state of the cadherin adhesive bond.
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                Author and article information

                Journal
                100890575
                21417
                Nat Cell Biol
                Nature cell biology
                1465-7392
                1476-4679
                18 February 2010
                21 February 2010
                March 2010
                1 September 2010
                : 12
                : 3
                : 247-256
                Affiliations
                [1 ] Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
                [2 ] MIT Ludwig Center for Molecular Oncology, Cambridge, MA 02142, USA
                [3 ] Medical Scientist Training Program, University of Virginia, Charlottesville, VA 22908, USA
                [4 ] Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
                [5 ] Department of Tumor Genetics, German Cancer Center, Im Neuenheimer Feld 280, Heidelberg, Germany
                [6 ] Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA
                Author notes
                [8 ]Correspondence should be addressed to R.A.W. ( weinberg@ 123456wi.mit.edu )
                [7]

                These authors contributed equally to this work.

                Article
                nihpa178418
                10.1038/ncb2024
                2845545
                20173740
                e983714c-1c6b-415a-97a3-4d7deb272884

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                History
                Funding
                Funded by: National Cancer Institute : NCI
                Award ID: K99 CA138572-01 ||CA
                Categories
                Article

                Cell biology
                Cell biology

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