title: MicroRNA-34c inversely couples the biological functions of the runt-related transcription factor RUNX2 and the tumor suppressor p53 in osteosarcoma.
abstract: Osteosarcoma (OS) is a primary bone tumor that is most prevalent during adolescence. RUNX2, which stimulates differentiation and suppresses proliferation of osteoblasts, is deregulated in OS. Here, we define pathological roles of RUNX2 in the etiology of OS and mechanisms by which RUNX2 expression is stimulated. RUNX2 is often highly expressed in human OS biopsies and cell lines. Small interference RNA-mediated depletion of RUNX2 inhibits growth of U2OS OS cells. RUNX2 levels are inversely linked to loss of p53 (which predisposes to OS) in distinct OS cell lines and osteoblasts. RUNX2 protein levels decrease upon stabilization of p53 with the MDM2 inhibitor Nutlin-3. Elevated RUNX2 protein expression is post-transcriptionally regulated and directly linked to diminished expression of several validated RUNX2 targeting microRNAs in human OS cells compared with mesenchymal progenitor cells. The p53-dependent miR-34c is the most significantly down-regulated RUNX2 targeting microRNAs in OS. Exogenous supplementation of miR-34c markedly decreases RUNX2 protein levels, whereas 3'-UTR reporter assays establish RUNX2 as a direct target of miR-34c in OS cells. Importantly, Nutlin-3-mediated stabilization of p53 increases expression of miR-34c and decreases RUNX2. Thus, a novel p53-miR-34c-RUNX2 network controls cell growth of osseous cells and is compromised in OS.
authors.affiliation: From the Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01655-0106.
authors.forename: Margaretha
authors.initials: M
authors.lastname: van der Deen
authors.affiliation: From the Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01655-0106,; Heisenberg-Group for Molecular Skeletal Biology, Department of Trauma, Hand, and Reconstructive Surgery, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
authors.forename: Hanna
authors.initials: H
authors.lastname: Taipaleenmäki
authors.affiliation: From the Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01655-0106.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: From the Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01655-0106.
authors.forename: Nadiya M
authors.initials: NM
authors.lastname: Teplyuk
authors.affiliation: From the Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01655-0106.
authors.forename: Anurag
authors.initials: A
authors.lastname: Gupta
authors.affiliation: From the Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01655-0106.
authors.forename: Senthilkumar
authors.initials: S
authors.lastname: Cinghu
authors.affiliation: Departments of Orthopedic Surgery and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Kristen
authors.initials: K
authors.lastname: Shogren
authors.affiliation: Departments of Orthopedic Surgery and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Avudaiappan
authors.initials: A
authors.lastname: Maran
authors.affiliation: Departments of Orthopedic Surgery and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Yaszemski
authors.affiliation: Institute of Medical Biology, Agency for Science, Technology, and Research, 8A Biomedical Grove, #06-06, Immunos, Singapore 138648.
authors.forename: Ling
authors.initials: L
authors.lastname: Ling
authors.affiliation: Institute of Medical Biology, Agency for Science, Technology, and Research, 8A Biomedical Grove, #06-06, Immunos, Singapore 138648,; Department of Orthopaedic Surgery, National University Hospital of Singapore, 1E Kent Ridge Road, NUHS Tower Block Level 11, Singapore 119228.
authors.forename: Simon M
authors.initials: SM
authors.lastname: Cool
authors.affiliation: Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117576.
authors.forename: David T
authors.initials: DT
authors.lastname: Leong
authors.affiliation: Medical Care Unit for Histology, Cytology, and Molecular Diagnostics, 54296 Trier, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Dierkes
authors.affiliation: Department of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
authors.forename: Jozef
authors.initials: J
authors.lastname: Zustin
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, United Kingdom,; Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, 12-01, Centre for Translational Medicine, Singapore 117599.
authors.forename: Manuel
authors.initials: M
authors.lastname: Salto-Tellez
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, 12-01, Centre for Translational Medicine, Singapore 117599.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Department of Biochemistry, School of Medicine, Chungbuk National University, Cheongju 361-763, South Korea.
authors.forename: Suk-Chul
authors.initials: SC
authors.lastname: Bae
authors.affiliation: Department of Paediatric Laboratory Medicine, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
authors.forename: Maria
authors.initials: M
authors.lastname: Zielenska
authors.affiliation: Department of Pathology and Molecular Medicine, Kingston General Hospital, Queen's University, Kingston, Ontario K7L 3N6 Canada.
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Squire
authors.affiliation: From the Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01655-0106,; Department of Biochemistry, HSRF 326, Vermont Cancer Center for Basic and Translational Research, University of Vermont Medical School, Burlington, Vermont 05405.
authors.forename: Jane B
authors.initials: JB
authors.lastname: Lian
authors.affiliation: From the Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01655-0106,; Department of Biochemistry, HSRF 326, Vermont Cancer Center for Basic and Translational Research, University of Vermont Medical School, Burlington, Vermont 05405.
authors.forename: Janet L
authors.initials: JL
authors.lastname: Stein
authors.affiliation: Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, and.
authors.forename: Gerard P
authors.initials: GP
authors.lastname: Zambetti
authors.affiliation: From the Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01655-0106.
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Jones
authors.affiliation: Millennium Institute on Immunology and Immunotherapy and Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: Mario
authors.initials: M
authors.lastname: Galindo
authors.affiliation: Heisenberg-Group for Molecular Skeletal Biology, Department of Trauma, Hand, and Reconstructive Surgery, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
authors.forename: Eric
authors.initials: E
authors.lastname: Hesse
authors.affiliation: From the Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01655-0106,; Department of Biochemistry, HSRF 326, Vermont Cancer Center for Basic and Translational Research, University of Vermont Medical School, Burlington, Vermont 05405,. Electronic address: gary.stein@uvm.edu.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Stein
authors.affiliation: From the Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01655-0106,; Departments of Orthopedic Surgery and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905,; Institute of Medical Biology, Agency for Science, Technology, and Research, 8A Biomedical Grove, #06-06, Immunos, Singapore 138648,; Department of Orthopaedic Surgery, National University Hospital of Singapore, 1E Kent Ridge Road, NUHS Tower Block Level 11, Singapore 119228,. Electronic address: vanwijnen.andre@mayo.edu.
authors.forename: Andre J
authors.initials: AJ
authors.lastname: van Wijnen
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000528:radiation effects; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage; D015536:Down-Regulation / Q000235:genetics / Q000528:radiation effects; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055550:Protein Stability / Q000528:radiation effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism*
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D050759:Cyclin-Dependent Kinase Inhibitor p21; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53
keywords: MicroRNA; Osteosarcoma; Transcription Factors; Tumor Suppressor Gene; p53