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Journal ArticleDOI

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

TL;DR: It is shown that miR-9, which is upregulated in breast cancer cells, directly targets CDH1, the E-cadherin-encoding messenger RNA, leading to increased cell motility and invasiveness, and a regulatory and signalling pathway involving a metastasis-promoting miRNA that is predicted to directly target expression of the key metastasis
Abstract: β-catenin signalling, which contributes to upregulated expression of the gene encoding vascular endothelial growth factor (VEGF); this leads, in turn, to increased tumour angiogenesis. Overexpression of miR-9 in otherwise non-metastatic breast tumour cells enables these cells to form pulmonary micrometastases in mice. Conversely, inhibiting miR-9 by 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, tumour grade and metastatic status. These findings uncover a regulatory and signalling pathway involving a metastasis-promoting miRNA that is predicted to directly target expression of the key metastasis-suppressing protein E-cadherin. Metastases are responsible for more than 90% of cancer-related mortality. These secondary growths arise through a multistep process that begins when cancer cells within primary tumours break away from neighbouring cells and invade the basement membrane 1 . This local invasion may frequently be triggered by contextual signals that carcinoma cells receive from the nearby stroma, causing them to undergo an epithelial–mesenchymal transition (EMT) 2 . Subsequently, metastasizing cells enter the circulation either directly or through lymphatics. Size constraints in the microvasculature cause many of these cells to be arrested at distant sites, where they may extravasate and enter the foreign tissue parenchyma. There they may remain dormant or, with low efficiency, proliferate from occult micrometastases to form angiogenic, clinically detectable metastases. The absence of EMT-inducing signals in the foreign microenvironment may cause such disseminated cells to revert to an epithelial phenotype by means of a mesenchymal–epithelial transition. Critical regulators of the metastatic process include both proteins and miRNAs 3,4

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Citations
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Journal ArticleDOI
TL;DR: The reprogramming of gene expression during EMT, as well as non-transcriptional changes, are initiated and controlled by signalling pathways that respond to extracellular cues, and the convergence of signalling pathways is essential for EMT.
Abstract: The transdifferentiation of epithelial cells into motile mesenchymal cells, a process known as epithelial-mesenchymal transition (EMT), is integral in development, wound healing and stem cell behaviour, and contributes pathologically to fibrosis and cancer progression. This switch in cell differentiation and behaviour is mediated by key transcription factors, including SNAIL, zinc-finger E-box-binding (ZEB) and basic helix-loop-helix transcription factors, the functions of which are finely regulated at the transcriptional, translational and post-translational levels. The reprogramming of gene expression during EMT, as well as non-transcriptional changes, are initiated and controlled by signalling pathways that respond to extracellular cues. Among these, transforming growth factor-β (TGFβ) family signalling has a predominant role; however, the convergence of signalling pathways is essential for EMT.

6,036 citations

Journal ArticleDOI
TL;DR: This work has shown that the regulation of miRNA metabolism and function by a range of mechanisms involving numerous protein–protein and protein–RNA interactions has an important role in the context-specific functions of miRNAs.
Abstract: MicroRNAs (miRNAs) are a large family of post-transcriptional regulators of gene expression that are ~21 nucleotides in length and control many developmental and cellular processes in eukaryotic organisms. Research during the past decade has identified major factors participating in miRNA biogenesis and has established basic principles of miRNA function. More recently, it has become apparent that miRNA regulators themselves are subject to sophisticated control. Many reports over the past few years have reported the regulation of miRNA metabolism and function by a range of mechanisms involving numerous protein-protein and protein-RNA interactions. Such regulation has an important role in the context-specific functions of miRNAs.

4,123 citations

Journal ArticleDOI
TL;DR: Dysregulation of these ncRNAs is being found to have relevance not only to tumorigenesis, but also to neurological, cardiovascular, developmental and other diseases, and there is great interest in therapeutic strategies to counteract these perturbations.
Abstract: The role of non-coding RNAs (ncRNAs) in disease is best understood for microRNAs in cancer. However, there is increasing interest in the disease-related roles of other ncRNAs — including piRNAs, snoRNAs, T-UCRs and lncRNAs — and in using this knowledge for therapy.

4,016 citations


Cites background from "miR-9, a MYC/MYCN-activated microRN..."

  • ...They act as sponges for cognate miRNAs, preventing their association with natural target...

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Journal ArticleDOI
30 Mar 2012-Cell
TL;DR: The richness of the understanding of MYC is reviewed, highlighting new biological insights and opportunities for cancer therapies.

2,572 citations


Cites background from "miR-9, a MYC/MYCN-activated microRN..."

  • ...Cancer cells are not just characterized by the propensity to proliferate with disregard to extracellular cues but also underscored by increased genomic instability, changes in morphology and function such as epithelial-mesenchymal transition (EMT), and an increased ability to metastasize....

    [...]

  • ...Myc has been linked to EMT and metastasis via its regulation of miRNA miR-9, which targets E-cadherin, as well as its ability to transactivate Bmi-1 which is linked to EMT (Ma et al., 2010; Song et al., 2009)....

    [...]

  • ...The miR-17 cluster contains miRNAs that target PTEN, thereby activating AKT, and those that target proapoptotic BimL or transcription factor E2F1 expression. miRNAs downstream of Myc have also been implicated in EMT and angiogenesis....

    [...]

Journal ArticleDOI
TL;DR: The EMT-associated reprogramming of cells not only suggests that fundamental changes may occur to several regulatory networks but also that an intimate interplay exists between them.
Abstract: Epithelial to mesenchymal transition (EMT) is essential for driving plasticity during development, but is an unintentional behaviour of cells during cancer progression. The EMT-associated reprogramming of cells not only suggests that fundamental changes may occur to several regulatory networks but also that an intimate interplay exists between them. Disturbance of a controlled epithelial balance is triggered by altering several layers of regulation, including the transcriptional and translational machinery, expression of non-coding RNAs, alternative splicing and protein stability.

2,136 citations

References
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Journal ArticleDOI
23 Jan 2004-Cell
TL;DR: Although they escaped notice until relatively recently, miRNAs comprise one of the more abundant classes of gene regulatory molecules in multicellular organisms and likely influence the output of many protein-coding genes.

32,946 citations

Journal ArticleDOI
14 Jan 2005-Cell
TL;DR: In a four-genome analysis of 3' UTRs, approximately 13,000 regulatory relationships were detected above the estimate of false-positive predictions, thereby implicating as miRNA targets more than 5300 human genes, which represented 30% of the gene set.

11,624 citations


"miR-9, a MYC/MYCN-activated microRN..." refers methods in this paper

  • ...In a preliminary survey we used several computational algorithms, including TargetSca...

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Journal ArticleDOI
16 May 2008-Cell
TL;DR: It is reported that the induction of an EMT in immortalized human mammary epithelial cells (HMLEs) results in the acquisition of mesenchymal traits and in the expression of stem-cell markers, and it is shown that those cells have an increased ability to form mammospheres, a property associated with mammARY epithelial stem cells.

8,052 citations


"miR-9, a MYC/MYCN-activated microRN..." refers background in this paper

  • ...Alternatively, the apparent ability of miR-9 to induce an EMT in HMLE cells might be explained by selection for a pre-existing rare mesenchymal subpopulation present within this particular cell lin...

    [...]

Journal ArticleDOI
Jean Paul Thiery1
TL;DR: Epithelial–mesenchymal transition provides a new basis for understanding the progression of carcinoma towards dedifferentiated and more malignant states.
Abstract: Without epithelial–mesenchymal transitions, in which polarized epithelial cells are converted into motile cells, multicellular organisms would be incapable of getting past the blastula stage of embryonic development. However, this important developmental programme has a more sinister role in tumour progression. Epithelial–mesenchymal transition provides a new basis for understanding the progression of carcinoma towards dedifferentiated and more malignant states.

6,362 citations

Journal ArticleDOI
TL;DR: PicTar, a computational method for identifying common targets of micro RNAs, is presented and widespread coordinate control executed by microRNAs is suggested, thus providing evidence for coordinate microRNA control in mammals.
Abstract: MicroRNAs are small noncoding RNAs that recognize and bind to partially complementary sites in the 3' untranslated regions of target genes in animals and, by unknown mechanisms, regulate protein production of the target transcript. Different combinations of microRNAs are expressed in different cell types and may coordinately regulate cell-specific target genes. Here, we present PicTar, a computational method for identifying common targets of microRNAs. Statistical tests using genome-wide alignments of eight vertebrate genomes, PicTar's ability to specifically recover published microRNA targets, and experimental validation of seven predicted targets suggest that PicTar has an excellent success rate in predicting targets for single microRNAs and for combinations of microRNAs. We find that vertebrate microRNAs target, on average, roughly 200 transcripts each. Furthermore, our results suggest widespread coordinate control executed by microRNAs. In particular, we experimentally validate common regulation of Mtpn by miR-375, miR-124 and let-7b and thus provide evidence for coordinate microRNA control in mammals.

4,660 citations

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