title: miR-579-3p controls melanoma progression and resistance to target therapy.
abstract: Therapy of melanoma patients harboring activating mutations in the BRAF (V-raf murine sarcoma viral oncogene homolog B1) oncogene with a combination of BRAF and MEK inhibitors is plagued by the development of drug resistance. Mutational events, as well as adaptive mechanisms, contribute to the development of drug resistance. In this context we uncover here the role of a miRNA, miR-579-3p. We first show that low expression of miR-579-3p is a negative prognostic factor correlating with poor survival. Expression levels of miR-579-3p decrease from nevi to stage III/IV melanoma samples and even further in cell lines resistant to BRAF/MEK inhibitors. Mechanistically, we demonstrate that miR-579-3p acts as an oncosuppressor by targeting the 3'UTR of two oncoproteins: BRAF and an E3 ubiquitin protein ligase, MDM2. Moreover miR-579-3p ectopic expression impairs the establishment of drug resistance in human melanoma cells. Finally, miR-579-3p is strongly down-regulated in matched tumor samples from patients before and after the development of resistance to targeted therapies.
authors: Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale", Naples 80131, Italy;
authors: Luigi
authors: L
authors: Fattore
authors: Dipartimento di Medicina Clinica e Molecolare, Sapienza Università di Roma, Rome 00161, Italy;
authors: Rita
authors: R
authors: Mancini
authors: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210;
authors: Mario
authors: M
authors: Acunzo
authors: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210;
authors: Giulia
authors: G
authors: Romano
authors: Department of Genetics, Genomic Sciences Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors: Alessandro
authors: A
authors: Laganà
authors: Dipartimento di Medicina Sperimentale e Clinica, Università degli Studi di Catanzaro "Magna Graecia", Catanzaro 88100, Italy;
authors: Maria Elena
authors: ME
authors: Pisanu
authors: Dipartimento di Medicina Sperimentale e Clinica, Università degli Studi di Catanzaro "Magna Graecia", Catanzaro 88100, Italy;
authors: Debora
authors: D
authors: Malpicci
authors: Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale", Naples 80131, Italy;
authors: Gabriele
authors: G
authors: Madonna
authors: Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale", Naples 80131, Italy;
authors: Domenico
authors: D
authors: Mallardo
authors: Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale", Naples 80131, Italy;
authors: Marilena
authors: M
authors: Capone
authors: Istituto Cantonale di Patologia, Servizio di Citologia Clinica, 6600 Locarno, Switzerland.
authors: Franco
authors: F
authors: Fulciniti
authors: Istituto Cantonale di Patologia, Servizio di Citologia Clinica, 6600 Locarno, Switzerland.
authors: Luca
authors: L
authors: Mazzucchelli
authors: Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale", Naples 80131, Italy;
authors: Gerardo
authors: G
authors: Botti
authors: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210; carlo.croce@osumc.edu g.ciliberto@istitutotumori.na.it.
authors: Carlo M
authors: CM
authors: Croce
authors: Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale", Naples 80131, Italy;
authors: Paolo Antonio
authors: PA
authors: Ascierto
authors: Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale", Naples 80131, Italy; carlo.croce@osumc.edu g.ciliberto@istitutotumori.na.it.
authors: Gennaro
authors: G
authors: Ciliberto
mesh_terms: D020413:3' Untranslated Regions; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics* / Q000378:metabolism; D011728:Pyridones / Q000627:therapeutic use; D011744:Pyrimidinones / Q000627:therapeutic use; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D013449:Sulfonamides / Q000627:therapeutic use; D016019:Survival Analysis; D000077484:Vemurafenib
chemical_list: D020413:3' Untranslated Regions; D000970:Antineoplastic Agents; D007211:Indoles; C000604992:MIRN579 microRNA, human; D035683:MicroRNAs; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; D013449:Sulfonamides; D000077484:Vemurafenib; C560077:trametinib; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: drug resistance; melanoma; miRNA; targeted therapy