title: A microRNA-1280/JAG2 network comprises a novel biological target in high-risk medulloblastoma.
abstract: Over-expression of PDGF receptors (PDGFRs) has been previously implicated in high-risk medulloblastoma (MB) pathogenesis. However, the exact biological functions of PDGFRα and PDGFRβ signaling in MB biology remain poorly understood. Here, we report the subgroup specific expression of PDGFRα and PDGFRβ and their associated biological pathways in MB tumors. c-MYC, a downstream target of PDGFRβ but not PDGFRα, is involved in PDGFRβ signaling associated with cell proliferation, cell death, and invasion. Concurrent inhibition of PDGFRβ and c-MYC blocks MB cell proliferation and migration synergistically. Integrated analysis of miRNA and miRNA targets regulated by both PDGFRβ and c-MYC reveals that increased expression of JAG2, a target of miR-1280, is associated with high metastatic dissemination at diagnosis and a poor outcome in MB patients. Our study may resolve the controversy on the role of PDGFRs in MB and unveils JAG2 as a key downstream effector of a PDGFRβ-driven signaling cascade and a potential therapeutic target.
authors.affiliation: Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA.
authors.forename: Fengfei
authors.initials: F
authors.lastname: Wang
authors.affiliation: Arthur and Sonia Labatt Brain Tumor Research Centre, Program in Developmental and Stem Cell Biology, Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Remke
authors.affiliation: Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA.
authors.forename: Kruttika
authors.initials: K
authors.lastname: Bhat
authors.affiliation: Brain Tumor Center & Neuro-Oncology Unit, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Eric T
authors.initials: ET
authors.lastname: Wong
authors.affiliation: Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA.
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Arthur and Sonia Labatt Brain Tumor Research Centre, Program in Developmental and Stem Cell Biology, Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada.
authors.forename: Vijay
authors.initials: V
authors.lastname: Ramaswamy
authors.affiliation: Arthur and Sonia Labatt Brain Tumor Research Centre, Program in Developmental and Stem Cell Biology, Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada.
authors.forename: Adrian
authors.initials: A
authors.lastname: Dubuc
authors.affiliation: Scott & White Neuroscience Institute, Texas A & M Health Science Center, Temple, TX 76508, USA.
authors.forename: Ekokobe
authors.initials: E
authors.lastname: Fonkem
authors.affiliation: Department of Computer Sciences, North Dakota State University, Fargo, ND 58105, USA.
authors.forename: Saeed
authors.initials: S
authors.lastname: Salem
authors.affiliation: Department of Physiology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100073, China.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA.
authors.forename: Tze-Chen
authors.initials: TC
authors.lastname: Hsieh
authors.affiliation: Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: O'Rourke
authors.affiliation: Department of Molecular Genetics and Microbiology, Shands Cancer Center, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Lizi
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Ophthalmology & Visual Sciences, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Li
authors.affiliation: Division of Pathology, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hawkins
authors.affiliation: Informatics Program, Children's Hospital Boston, Harvard Medical School, Boston 02115, MA, USA.
authors.forename: Isaac S
authors.initials: IS
authors.lastname: Kohane
authors.affiliation: Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Molecular Biology, University of North Dakota, Grand Forks, ND 58202, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.affiliation: Arthur and Sonia Labatt Brain Tumor Research Centre, Program in Developmental and Stem Cell Biology, Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.affiliation: Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA.
authors.forename: Erxi
authors.initials: E
authors.lastname: Wu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D016923:Cell Death; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D019295:Computational Biology; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D000072101:Jagged-2 Protein; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism* / Q000556:secondary / Q000628:therapy; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D009361:Neoplasm Invasiveness; D011379:Prognosis; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D000067492:RNAi Therapeutics; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D036341:Intercellular Signaling Peptides and Proteins; C490504:JAG2 protein, human; D000072101:Jagged-2 Protein; C000603194:MIRN-1280 microRNA, human; C489427:MYC protein, human; D008565:Membrane Proteins; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta