title: Targeting Notch signalling by the conserved miR-8/200 microRNA family in development and cancer cells.
abstract: Notch signalling is crucial for the correct development and growth of numerous organs and tissues, and when subverted it can cause cancer. Loss of miR-8/200 microRNAs (miRNAs) is commonly observed in advanced tumours and correlates with their invasion and acquisition of stem-like properties. Here, we show that this miRNA family controls Notch signalling activation in Drosophila and human cells. In an overexpression screen, we identified the Drosophila miR-8 as a potent inhibitor of Notch-induced overgrowth and tumour metastasis. Gain and loss of mir-8 provoked developmental defects reminiscent of impaired Notch signalling and we demonstrated that miR-8 directly inhibits Notch ligand Serrate. Likewise, miR-200c and miR-141 directly inhibited JAGGED1, impeding proliferation of human metastatic prostate cancer cells. It has been suggested that JAGGED1 may also be important for metastases. Although in metastatic cancer cells, JAGGED1 modestly regulated ZEB1, the miR-200c's target in invasion, studies in Drosophila revealed that only concurrent overexpression of Notch and Zfh1/ZEB1 induced tumour metastases. Together, these data define a new way to attenuate or boost Notch signalling that may have clinical interest.
authors.affiliation: Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas (CSIC) and Universidad Miguel Hernández (UMH), Campus de Sant Joan, Sant Joan, Alicante, Spain.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Vallejo
authors.forename: Esther
authors.initials: E
authors.lastname: Caparros
authors.forename: Maria
authors.initials: M
authors.lastname: Dominguez
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D002478:Cells, Cultured; D017124:Conserved Sequence; D029721:Drosophila Proteins; D004331:Drosophila melanogaster / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D004625:Embryo, Nonmammalian; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D048788:Growth and Development / Q000187:drug effects / Q000235:genetics*; D045325:HCT116 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology*; D005810:Multigene Family / Q000502:physiology; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000235:genetics; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction
chemical_list: D002135:Calcium-Binding Proteins; D029721:Drosophila Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; C533896:MIRN200 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D051880:Receptors, Notch; C000606278:Ser protein, Drosophila; D000072099:Serrate-Jagged Proteins; C526630:MIRN8 microRNA, Drosophila