title: miR-182 integrates apoptosis, growth, and differentiation programs in glioblastoma.
abstract: Glioblastoma multiforme (GBM) is a lethal, therapy-resistant brain cancer consisting of numerous tumor cell subpopulations, including stem-like glioma-initiating cells (GICs), which contribute to tumor recurrence following initial response to therapy. Here, we identified miR-182 as a regulator of apoptosis, growth, and differentiation programs whose expression level is correlated with GBM patient survival. Repression of Bcl2-like12 (Bcl2L12), c-Met, and hypoxia-inducible factor 2α (HIF2A) is of central importance to miR-182 anti-tumor activity, as it results in enhanced therapy susceptibility, decreased GIC sphere size, expansion, and stemness in vitro. To evaluate the tumor-suppressive function of miR-182 in vivo, we synthesized miR-182-based spherical nucleic acids (182-SNAs); i.e., gold nanoparticles covalently functionalized with mature miR-182 duplexes. Intravenously administered 182-SNAs penetrated the blood-brain/blood-tumor barriers (BBB/BTB) in orthotopic GBM xenografts and selectively disseminated throughout extravascular glioma parenchyma, causing reduced tumor burden and increased animal survival. Our results indicate that harnessing the anti-tumor activities of miR-182 via safe and robust delivery of 182-SNAs represents a novel strategy for therapeutic intervention in GBM.
authors.affiliation: Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Chicago, Illinois 60611, USA; The Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois 60611, USA;
authors.forename: Fotini M
authors.initials: FM
authors.lastname: Kouri
authors.affiliation: Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Chicago, Illinois 60611, USA; The Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois 60611, USA;
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Hurley
authors.affiliation: AuraSense Therapeutics, Skokie, Illinois 60077, USA;
authors.forename: Weston L
authors.initials: WL
authors.lastname: Daniel
authors.affiliation: Department of Chemistry, Northwestern University, Evanston, Illinois 60208, USA; International Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, USA;
authors.forename: Emily S
authors.initials: ES
authors.lastname: Day
authors.affiliation: Division Hematology/Oncology, Feinberg School of Medicine, Chicago, Illinois 60611, USA; The Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois 60611, USA;
authors.forename: Youjia
authors.initials: Y
authors.lastname: Hua
authors.affiliation: Department of Chemistry, Northwestern University, Evanston, Illinois 60208, USA; International Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, USA;
authors.forename: Liangliang
authors.initials: L
authors.lastname: Hao
authors.affiliation: Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Chicago, Illinois 60611, USA; The Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois 60611, USA;
authors.forename: Chian-Yu
authors.initials: CY
authors.lastname: Peng
authors.affiliation: Department of Chemistry, Northwestern University, Evanston, Illinois 60208, USA; International Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, USA;
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Merkel
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois 60611, USA;
authors.forename: Markus A
authors.initials: MA
authors.lastname: Queisser
authors.affiliation: Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Chicago, Illinois 60611, USA; The Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois 60611, USA;
authors.forename: Carissa
authors.initials: C
authors.lastname: Ritner
authors.affiliation: The Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA; Harvard Medical School, Boston, Massachusetts 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA; Department of Genomic Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA; Institute for Applied Cancer Science, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
authors.forename: Hailei
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, 60611, USA.
authors.forename: C David
authors.initials: CD
authors.lastname: James
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois 60611, USA;
authors.forename: Jacob I
authors.initials: JI
authors.lastname: Sznajder
authors.affiliation: The Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA; Harvard Medical School, Boston, Massachusetts 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA; Department of Genomic Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA; Institute for Applied Cancer Science, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
authors.forename: Lynda
authors.initials: L
authors.lastname: Chin
authors.affiliation: AuraSense Therapeutics, Skokie, Illinois 60077, USA;
authors.forename: David A
authors.initials: DA
authors.lastname: Giljohann
authors.affiliation: Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Chicago, Illinois 60611, USA; The Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois 60611, USA;
authors.forename: John A
authors.initials: JA
authors.lastname: Kessler
authors.affiliation: Division Hematology/Oncology, Feinberg School of Medicine, Chicago, Illinois 60611, USA; The Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois 60611, USA;
authors.forename: Marcus E
authors.initials: ME
authors.lastname: Peter
authors.affiliation: Department of Chemistry, Northwestern University, Evanston, Illinois 60208, USA; International Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, USA;
authors.forename: Chad A
authors.initials: CA
authors.lastname: Mirkin
authors.affiliation: Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Chicago, Illinois 60611, USA; The Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois 60611, USA; Department of Chemistry, Northwestern University, Evanston, Illinois 60208, USA; International Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, USA; a-stegh@northwestern.edu.
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Stegh
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000235:genetics*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D002454:Cell Differentiation / Q000235:genetics*; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis
chemical_list: D000970:Antineoplastic Agents; C430100:BCL2L12 protein, human; D035683:MicroRNAs; C538984:Mirn182 microRNA, human; D009124:Muscle Proteins; D019253:Proto-Oncogene Proteins c-bcl-2
keywords: Bcl2L12; HIF2A; c-Met; glioblastoma; miR-182; nanotechnology; spherical nucleic acids
references.citation: Dev Cell. 2006 Oct;11(4):441-50
references.pmid: 17011485
references.citation: Nat Rev Cancer. 2006 Aug;6(8):637-45
references.pmid: 16862193
references.citation: Genes Dev. 2007 Jan 1;21(1):98-111
references.pmid: 17210792
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 31;104(31):12867-72
references.pmid: 17646646
references.citation: J Biol Chem. 2007 Aug 24;282(34):25053-66
references.pmid: 17597072
references.citation: J Neurosurg. 2007 Sep;107(3):610-6
references.pmid: 17886562
references.citation: Science. 2007 Oct 12;318(5848):287-90
references.pmid: 17872411
references.citation: Curr Neurol Neurosci Rep. 2008 May;8(3):235-41
references.pmid: 18541119
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10703-8
references.pmid: 18669646
references.citation: Cell Cycle. 2008 Sep 15;7(18):2833-9
references.pmid: 18769159
references.citation: Nature. 2008 Oct 23;455(7216):1061-8
references.pmid: 18772890
references.citation: Nano Lett. 2009 Jan;9(1):308-11
references.pmid: 19099465
references.citation: J Am Chem Soc. 2009 Feb 18;131(6):2072-3
references.pmid: 19170493
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):1814-9
references.pmid: 19188590
references.citation: Lancet Oncol. 2009 May;10(5):459-66
references.pmid: 19269895
references.citation: Cancer Cell. 2009 Jun 2;15(6):501-13
references.pmid: 19477429
references.citation: Nat Biotechnol. 2009 Oct;27(10):914-5
references.pmid: 19816447
references.citation: Cell Cycle. 2009 Nov 15;8(22):3611-2
references.pmid: 19855181
references.citation: J Clin Oncol. 2009 Dec 1;27(34):5848-56
references.pmid: 19884536
references.citation: BMC Cancer. 2009;9:401
references.pmid: 19922656
references.citation: Mol Pharm. 2009 Nov-Dec;6(6):1934-40
references.pmid: 19810673
references.citation: Cancer Cell. 2010 Jan 19;17(1):98-110
references.pmid: 20129251
references.citation: Genes Dev. 2010 Oct 1;24(19):2194-204
references.pmid: 20837658
references.citation: Cell Cycle. 2011 Jan 1;10(1):33-8
references.pmid: 21200141
references.citation: Dev Dyn. 2011 Apr;240(4):808-19
references.pmid: 21360794
references.citation: Cancer Res. 2011 May 1;71(9):3387-99
references.pmid: 21385897
references.citation: Acta Neuropathol. 2012 Apr;123(4):539-52
references.pmid: 22402744
references.citation: FEBS J. 2012 Apr;279(7):1252-60
references.pmid: 22325466
references.citation: Genes Dev. 2012 Apr 15;26(8):756-84
references.pmid: 22508724
references.citation: Cancer J. 2012 May-Jun;18(3):215-22
references.pmid: 22647357
references.citation: PLoS One. 2012;7(7):e40967
references.pmid: 22848417
references.citation: PLoS One. 2012;7(8):e43569
references.pmid: 22927992
references.citation: Mol Syst Biol. 2012;8:605
references.pmid: 22929615
references.citation: Int J Pharm. 2012 Oct 15;436(1-2):299-310
references.pmid: 22721856
references.citation: J Pathol. 2012 Oct;228(2):204-15
references.pmid: 22322863
references.citation: Neoplasia. 2012 Sep;14(9):868-79
references.pmid: 23019418
references.citation: J Clin Invest. 2012 Oct;122(10):3563-78
references.pmid: 23006329
references.citation: PLoS One. 2012;7(11):e51056
references.pmid: 23226455
references.citation: Clin Pharmacol Ther. 2013 Jan;93(1):98-104
references.pmid: 23212103
references.citation: PLoS One. 2013;8(1):e55502
references.pmid: 23383207
references.citation: Neuro Oncol. 2013 Mar;15(3):319-29
references.pmid: 23328812
references.citation: Clin Cancer Res. 2013 Apr 15;19(8):2154-62
references.pmid: 23459718
references.citation: Int J Cancer. 2013 Aug 1;133(3):544-55
references.pmid: 23354685
references.citation: Cancer Res. 2013 Jun 1;73(11):3193-9
references.pmid: 23695554
references.citation: PLoS One. 2013;8(7):e68982
references.pmid: 23874837
references.citation: Sci Transl Med. 2013 Oct 30;5(209):209ra152
references.pmid: 24174328
references.citation: PLoS One. 2014;9(1):e84146
references.pmid: 24404152
references.citation: Mol Cancer. 2014;13:109
references.pmid: 24886554
references.citation: Nature. 2014 Jun 19;510(7505):393-6
references.pmid: 24870234
references.citation: PLoS One. 2014;9(7):e101239
references.pmid: 25010047
references.citation: Tumour Biol. 2014 Jul;35(7):6557-65
references.pmid: 24691972
references.citation: Oncogene. 2005 Aug 29;24(37):5722-30
references.pmid: 16123805
references.citation: Nat Rev Mol Cell Biol. 2005 May;6(5):376-85
references.pmid: 15852042
references.citation: Breast Cancer Res. 2014;16(6):473
references.pmid: 25394902
references.citation: Neurosurg Focus. 2006;20(4):E17
references.pmid: 16709022
references.citation: Nature. 2006 Dec 7;444(7120):756-60
references.pmid: 17051156