title: Silencing of the miR-17~92 cluster family inhibits medulloblastoma progression.
abstract: Medulloblastoma, originating in the cerebellum, is the most common malignant brain tumor in children. Medulloblastoma consists of four major groups where constitutive activation of the Sonic Hedgehog (SHH) signaling pathway is a hallmark of one group. Mouse and human SHH medulloblastomas exhibit increased expression of microRNAs encoded by the miR-17~92 and miR-106b~25 clusters compared with granule progenitors and postmitotic granule neurons. Here, we assessed the therapeutic potential of 8-mer seed-targeting locked nucleic acid (LNA)-modified anti-miR oligonucleotides, termed tiny LNAs, that inhibit microRNA seed families expressed by miR-17~92 and miR-106b~25 in two mouse models of SHH medulloblastomas. We found that tumor cells (medulloblastoma cells) passively took up 8-mer LNA-anti-miRs and specifically inhibited targeted microRNA seed-sharing family members. Inhibition of miR-17 and miR-19a seed families by anti-miR-17 and anti-miR-19, respectively, resulted in diminished tumor cell proliferation in vitro. Treatment of mice with systemic delivery of anti-miR-17 and anti-miR-19 reduced tumor growth in flank and brain allografts in vivo and prolonged the survival of mice with intracranial transplants, suggesting that inhibition of the miR-17~92 cluster family by 8-mer LNA-anti-miRs might be considered for the treatment of SHH medulloblastomas.
authors.affiliation: Authors' Affiliations: Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee; Santaris Pharma, Hørsholm; and Department of Haematology, Aalborg University Hospital, Copenhagen, Denmark.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Murphy
authors.forename: Susanna
authors.initials: S
authors.lastname: Obad
authors.forename: Laure
authors.initials: L
authors.lastname: Bihannic
authors.forename: Olivier
authors.initials: O
authors.lastname: Ayrault
authors.forename: Frederique
authors.initials: F
authors.lastname: Zindy
authors.forename: Sakari
authors.initials: S
authors.lastname: Kauppinen
authors.forename: Martine F
authors.initials: MF
authors.lastname: Roussel
mesh_terms: D000818:Animals; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000473:pathology*; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000235:genetics; D005810:Multigene Family / Q000187:drug effects; D009841:Oligonucleotides / Q000494:pharmacology; D034622:RNA Interference; D062085:RNA, Long Noncoding; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C568997:MIR17HG, human; D035683:MicroRNAs; D009841:Oligonucleotides; D062085:RNA, Long Noncoding; C477371:locked nucleic acid