title: miR-146a promotes the initiation and progression of melanoma by activating Notch signaling.
abstract: Oncogenic mutations in BRAF and NRAS occur in 70% of melanomas. In this study, we identify a microRNA, miR-146a, that is highly upregulated by oncogenic BRAF and NRAS. Expression of miR-146a increases the ability of human melanoma cells to proliferate in culture and form tumors in mice, whereas knockdown of miR-146a has the opposite effects. We show these oncogenic activities are due to miR-146a targeting the NUMB mRNA, a repressor of Notch signaling. Previous studies have shown that pre-miR-146a contains a single nucleotide polymorphism (C>G rs2910164). We find that the ability of pre-miR-146a/G to activate Notch signaling and promote oncogenesis is substantially higher than that of pre-miR-146a/C. Analysis of melanoma cell lines and matched patient samples indicates that during melanoma progression pre-miR-146a/G is enriched relative to pre-miR-146a/C, resulting from a C-to-G somatic mutation in pre-miR-146a/C. Collectively, our results reveal a central role for miR-146a in the initiation and progression of melanoma. DOI: http://dx.doi.org/10.7554/eLife.01460.001.
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, United States.
authors.forename: Matteo
authors.initials: M
authors.lastname: Forloni
authors.forename: Shaillay Kumar
authors.initials: SK
authors.lastname: Dogra
authors.forename: Yuying
authors.initials: Y
authors.lastname: Dong
authors.forename: Darryl
authors.initials: D
authors.lastname: Conte
authors.forename: Jianhong
authors.initials: J
authors.lastname: Ou
authors.forename: Lihua Julie
authors.initials: LJ
authors.lastname: Zhu
authors.forename: April
authors.initials: A
authors.lastname: Deng
authors.forename: Meera
authors.initials: M
authors.lastname: Mahalingam
authors.forename: Michael R
authors.initials: MR
authors.lastname: Green
authors.forename: Narendra
authors.initials: N
authors.lastname: Wajapeyee
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden
chemical_list: C542542:MIRN146 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; C113026:NUMB protein, human; D051880:Receptors, Notch; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human
keywords: BRAF; NRAS; melanoma; miRNA