title: MicroRNAs in the imprinted DLK1-DIO3 region repress the epithelial-to-mesenchymal transition by targeting the TWIST1 protein signaling network.
abstract: Development of metastatic disease accounts for the vast majority of cancer-related deaths. Nevertheless, few treatments exist that are designed to specifically inhibit processes that drive tumor metastasis. The imprinted DLK1-DIO3 region contains tumor-suppressing miRNAs, but their identity and function remain indeterminate. In this study we identify seven miRNAs in the imprinted DLK1-DIO3 region that function cooperatively to repress the epithelial-to-mesenchymal transition, a critical step that drives tumor metastasis, as well as proliferation of carcinoma cells. These seven miRNAs (miRs 300, 382, 494, 495, 539, 543, and 544) repress a signaling network comprising TWIST1, BMI1, ZEB1/2, and miR-200 family miRNAs and silencing of the cluster, which occurs via hypermethylation of upstream CpG islands in human ductal carcinomas, confers morphological, molecular, and function changes consistent with an epithelial-to-mesenchymal transition. Moreover, ectopic expression of miR-544 independently inhibited proliferation of numerous tumor cell lines by inducing the ATM cell cycle checkpoint pathway. These results establish the DLKI-DIO3 miRNA cluster as a critical checkpoint regulating tumor growth and metastasis and implicate epigenetic modification of the cluster in driving tumor progression. These results also suggest that promoter methylation status and miRNA expression levels represent new diagnostic tools and therapeutic targets to predict and inhibit, respectively, tumor metastasis in carcinoma patients.
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Haga
authors.forename: Donald G
authors.initials: DG
authors.lastname: Phinney
mesh_terms: D015703:Antigens, CD; D064007:Ataxia Telangiectasia Mutated Proteins; D001483:Base Sequence; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D048430:Cell Shape / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056426:Genetic Loci / Q000235:genetics*; D018392:Genomic Imprinting / Q000235:genetics*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000235:genetics; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; C069077:BMI1 protein, human; C513384:CDH1 protein, human; D015820:Cadherins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D025521:Tumor Suppressor Proteins; D051879:Twist-Related Protein 1; D063150:Polycomb Repressive Complex 1; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases