title: The Cancer Genome Atlas Analysis Predicts MicroRNA for Targeting Cancer Growth and Vascularization in Glioblastoma.
abstract: Using in silico analysis of The Cancer Genome Atlas (TCGA), we identified microRNAs associated with glioblastoma (GBM) survival, and predicted their functions in glioma growth and progression. Inhibition of two "risky" miRNAs, miR-148a and miR-31, in orthotopic xenograft GBM mouse models suppressed tumor growth and thereby prolonged animal survival. Intracranial tumors treated with uncomplexed miR-148a and miR-31 antagomirs exhibited reduced proliferation, stem cell depletion, and normalized tumor vasculature. Growth-promoting functions of these two miRNAs were, in part, mediated by the common target, the factor inhibiting hypoxia-inducible factor 1 (FIH1), and the downstream pathways involving hypoxia-inducible factor HIF1α and Notch signaling. Therefore, miR-31 and miR-148a regulate glioma growth by maintaining tumor stem cells and their niche, and providing the tumor a way to activate angiogenesis even in a normoxic environment. This is the first study that demonstrates intratumoral uptake and growth-inhibiting effects of uncomplexed antagomirs in orthotopic glioma.
authors.affiliation: Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Hon-Kit Andus
authors.initials: HA
authors.lastname: Wong
authors.affiliation: Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Rachid El
authors.initials: RE
authors.lastname: Fatimy
authors.affiliation: Department of Epidemiology and Biostatistics, University of California, San Francisco, California, USA.
authors.forename: Courtney
authors.initials: C
authors.lastname: Onodera
authors.affiliation: Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Zhiyun
authors.initials: Z
authors.lastname: Wei
authors.affiliation: Cancer Research and Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Yi
authors.affiliation: Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Athul
authors.initials: A
authors.lastname: Mohan
authors.affiliation: Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Sindhuja
authors.initials: S
authors.lastname: Gowrisankaran
authors.affiliation: Regulus Therapeutics, Inc., San Diego, California, USA.
authors.forename: Priya
authors.initials: P
authors.lastname: Karmali
authors.affiliation: Regulus Therapeutics, Inc., San Diego, California, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Marcusson
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Wakimoto
authors.affiliation: Cancer Research and Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Stephens
authors.affiliation: Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Uhlmann
authors.affiliation: Department of Epidemiology and Biostatistics, University of California, San Francisco, California, USA; Current Address: Department of Bioengineering, University of Illinois, Urbana-Champaign, Illinois, USA; Current Address: Department of Physics, University of Illinois, Urbana-Champaign, Illinois, USA.
authors.forename: Jun S
authors.initials: JS
authors.lastname: Song
authors.affiliation: Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Bakhos
authors.initials: B
authors.lastname: Tannous
authors.affiliation: Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. Electronic address: akrichevsky@rics.bwh.harvard.edu.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Krichevsky
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology; D009841:Oligonucleotides / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C550570:MIRN148 microRNA, human; C534612:MIRN31 microRNA, human; D035683:MicroRNAs; D009841:Oligonucleotides