title: Antagomir-17-5p abolishes the growth of therapy-resistant neuroblastoma through p21 and BIM.
abstract: We identified a key oncogenic pathway underlying neuroblastoma progression: specifically, MYCN, expressed at elevated level, transactivates the miRNA 17-5p-92 cluster, which inhibits p21 and BIM translation by interaction with their mRNA 3' UTRs. Overexpression of miRNA 17-5p-92 cluster in MYCN-not-amplified neuroblastoma cells strongly augments their in vitro and in vivo tumorigenesis. In vitro or in vivo treatment with antagomir-17-5p abolishes the growth of MYCN-amplified and therapy-resistant neuroblastoma through p21 and BIM upmodulation, leading to cell cycling blockade and activation of apoptosis, respectively. In primary neuroblastoma, the majority of cases show a rise of miR-17-5p level leading to p21 downmodulation, which is particularly severe in patients with MYCN amplification and poor prognosis. Altogether, our studies demonstrate for the first time that antagomir treatment can abolish tumor growth in vivo, specifically in therapy-resistant neuroblastoma.
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy. lfontana@iss.it
authors.forename: Laura
authors.initials: L
authors.lastname: Fontana
authors.forename: Micol E
authors.initials: ME
authors.lastname: Fiori
authors.forename: Sonia
authors.initials: S
authors.lastname: Albini
authors.forename: Loredana
authors.initials: L
authors.lastname: Cifaldi
authors.forename: Serena
authors.initials: S
authors.lastname: Giovinazzi
authors.forename: Matteo
authors.initials: M
authors.lastname: Forloni
authors.forename: Renata
authors.initials: R
authors.lastname: Boldrini
authors.forename: Alberto
authors.initials: A
authors.lastname: Donfrancesco
authors.forename: Valentina
authors.initials: V
authors.lastname: Federici
authors.forename: Patrizio
authors.initials: P
authors.lastname: Giacomini
authors.forename: Cesare
authors.initials: C
authors.lastname: Peschle
authors.forename: Doriana
authors.initials: D
authors.lastname: Fruci
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001483:Base Sequence; D000072224:Bcl-2-Like Protein 11; D045744:Cell Line, Tumor; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D016259:Genes, myc; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000627:therapeutic use*; D009447:Neuroblastoma / Q000188:drug therapy / Q000473:pathology*; D015689:Oncogene Protein p21(ras) / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D015689:Oncogene Protein p21(ras)