title: MiR-34a deficiency accelerates medulloblastoma formation in vivo.
abstract: Previous studies have evaluated the role of miRNAs in cancer initiation and progression. MiR-34a was found to be downregulated in several tumors, including medulloblastomas. Here we employed targeted transgenesis to analyze the function of miR-34a in vivo. We generated mice with a constitutive deletion of the miR-34a gene. These mice were devoid of mir-34a expression in all analyzed tissues, but were viable and fertile. A comprehensive standardized phenotypic analysis including more than 300 single parameters revealed no apparent phenotype. Analysis of miR-34a expression in human medulloblastomas and medulloblastoma cell lines revealed significantly lower levels than in normal human cerebellum. Re-expression of miR-34a in human medulloblastoma cells reduced cell viability and proliferation, induced apoptosis and downregulated the miR-34a target genes, MYCN and SIRT1. Activation of the Shh pathway by targeting SmoA1 transgene overexpression causes medulloblastoma in mice, which is dependent on the presence and upregulation of Mycn. Analysis of miR-34a in medulloblastomas derived from ND2:SmoA1(tg) mice revealed significant suppression of miR-34a compared to normal cerebellum. Tumor incidence was significantly increased and tumor formation was significantly accelerated in mice transgenic for SmoA1 and lacking miR-34a. Interestingly, Mycn and Sirt1 were strongly expressed in medulloblastomas derived from these mice. We here demonstrate that miR-34a is dispensable for normal development, but that its loss accelerates medulloblastomagenesis. Strategies aiming to re-express miR-34a in tumors could, therefore, represent an efficient therapeutic option.
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, Hufelandstr. 55 45147, Essen, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), D-69120, Heidelberg, Germany.
authors.forename: Theresa
authors.initials: T
authors.lastname: Thor
authors.forename: Annette
authors.initials: A
authors.lastname: Künkele
authors.forename: Kristian W
authors.initials: KW
authors.lastname: Pajtler
authors.forename: Annika K
authors.initials: AK
authors.lastname: Wefers
authors.forename: Harald
authors.initials: H
authors.lastname: Stephan
authors.forename: Pieter
authors.initials: P
authors.lastname: Mestdagh
authors.forename: Lukas
authors.initials: L
authors.lastname: Heukamp
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hartmann
authors.forename: Jo
authors.initials: J
authors.lastname: Vandesompele
authors.forename: Natalie
authors.initials: N
authors.lastname: Sadowski
authors.forename: Lore
authors.initials: L
authors.lastname: Becker
authors.forename: Lillian
authors.initials: L
authors.lastname: Garrett
authors.forename: Sabine M
authors.initials: SM
authors.lastname: Hölter
authors.forename: Marion
authors.initials: M
authors.lastname: Horsch
authors.forename: Julia
authors.initials: J
authors.lastname: Calzada-Wack
authors.forename: Tanja
authors.initials: T
authors.lastname: Klein-Rodewald
authors.forename: Ildiko
authors.initials: I
authors.lastname: Racz
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmer
authors.forename: Johannes
authors.initials: J
authors.lastname: Beckers
authors.forename: Frauke
authors.initials: F
authors.lastname: Neff
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
authors.forename: Pasqualino
authors.initials: P
authors.lastname: De Antonellis
authors.forename: Massimo
authors.initials: M
authors.lastname: Zollo
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wurst
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.forename: Valérie
authors.initials: V
authors.lastname: Gailus-Durner
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schüller
authors.forename: Martin Hrabě
authors.initials: MH
authors.lastname: de Angelis
authors.forename: Angelika
authors.initials: A
authors.lastname: Eggert
authors.forename: Alexander
authors.initials: A
authors.lastname: Schramm
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Schulte
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002531:Cerebellum / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D055786:Gene Knockout Techniques; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D015398:Signal Transduction
chemical_list: C522425:MIRN34 microRNA, human; C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs
keywords: MYCN; ND2:SmoA1; miR-34a; pediatric brain tumors