A microRNA-1280/JAG2 network comprises a novel biological target in high-risk medulloblastoma
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Fengfei Wang1,*, Marc Remke2,*, Kruttika Bhat1,*, Eric T. Wong3, Shuang Zhou1, Vijay Ramaswamy2, Adrian Dubuc2, Ekokobe Fonkem4, Saeed Salem5, Hongbing Zhang6, Tze-chen Hsieh7, Stephen T. O’Rourke1, Lizi Wu8, David W. Li9, Cynthia Hawkins10, Isaac S. Kohane11, Joseph M. Wu7, Min Wu12, Michael D. Taylor2, Erxi Wu1
1Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA
2Arthur 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
3Brain Tumor Center & Neuro-Oncology Unit, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
4Scott & White Neuroscience Institute, Texas A & M Health Science Center, Temple, TX 76508, USA
5Department of Computer Sciences, North Dakota State University, Fargo, ND 58105, USA
6Department 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
7Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA
8Department of Molecular Genetics and Microbiology, Shands Cancer Center, University of Florida, Gainesville, FL 32610, USA
9Department of Ophthalmology & Visual Sciences, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
10Division of Pathology, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
11Informatics Program, Children’s Hospital Boston, Harvard Medical School, Boston 02115, MA, USA
12Department of Biochemistry and Molecular Biology, University of North Dakota, Grand Forks, ND 58202, USA
*These authors have contributed equally to this work
Michael D. Taylor, e-mail: [email protected]
Erxi Wu, e-mail: [email protected]
Keywords: PDGFR, c-MYC, JAG2, miR-1280, medulloblastoma, target therapy
Received: September 21, 2014 Accepted: November 19, 2014 Published: December 17, 2014
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.
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