title: The WIP1 oncogene promotes progression and invasion of aggressive medulloblastoma variants.
abstract: Recent studies suggest that medulloblastoma, the most common malignant brain tumor of childhood, is comprised of four disease variants. The WIP1 oncogene is overexpressed in Group 3 and 4 tumors, which contain medulloblastomas with the most aggressive clinical behavior. Our data demonstrate increased WIP1 expression in metastatic medulloblastomas, and inferior progression-free and overall survival of patients with WIP1 high-expressing medulloblastoma. Microarray analysis identified upregulation of genes involved in tumor metastasis, including the G protein-coupled receptor CXCR4, in medulloblastoma cells with high WIP1 expression. Stimulation with the CXCR4 ligand SDF1α activated PI-3 kinase signaling, and promoted growth and invasion of WIP1 high-expressing medulloblastoma cells in a p53-dependent manner. When xenografted into the cerebellum of immunodeficient mice, medulloblastoma cells with stable or endogenous high WIP1 expression exhibited strong expression of CXCR4 and activated AKT in primary and invasive tumor cells. WIP1 or CXCR4 knockdown inhibited medulloblastoma growth and invasion. WIP1 knockdown also improved the survival of mice xenografted with WIP1 high-expressing medulloblastoma cells. WIP1 knockdown inhibited cell surface localization of CXCR4 by suppressing expression of the G protein receptor kinase 5, GRK5. Restoration of wild-type GRK5 promoted Ser339 phosphorylation of CXCR4 and inhibited the growth of WIP1-stable medulloblastoma cells. Conversely, GRK5 knockdown inhibited Ser339 phosphorylation of CXCR4, increased cell surface localization of CXCR4 and promoted the growth of medulloblastoma cells with low WIP1 expression. These results demonstrate crosstalk among WIP1, CXCR4 and GRK5, which may be important for the aggressive phenotype of a subclass of medulloblastomas in children.
authors.affiliation: Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Buss
authors.affiliation: Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumour Research Center, Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Remke
authors.affiliation: Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Gandhi
authors.affiliation: Department of Pathology, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Schniederjan
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Kool
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: P A
authors.initials: PA
authors.lastname: Northcott
authors.affiliation: 1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany [2] Department of Pediatric Hematology, Oncology and Immunology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: S M
authors.initials: SM
authors.lastname: Pfister
authors.affiliation: Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumour Research Center, Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: M D
authors.initials: MD
authors.lastname: Taylor
authors.affiliation: Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: R C
authors.initials: RC
authors.lastname: Castellino
mesh_terms: D000293:Adolescent; D000818:Animals; D045744:Cell Line, Tumor; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000473:pathology*; D054426:Chemokine CXCL2 / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D005260:Female; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007223:Infant; D008297:Male; D008527:Medulloblastoma / Q000235:genetics / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D010749:Phosphoprotein Phosphatases / Q000235:genetics* / Q000378:metabolism; D000071636:Protein Phosphatase 2C; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D055815:Young Adult
chemical_list: C499706:CXCL2 protein, human; C527276:CXCR4 protein, human; D054426:Chemokine CXCL2; D019718:Receptors, CXCR4; D054774:G-Protein-Coupled Receptor Kinase 5; C517898:GRK5 protein, human; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; C000607468:Ppm1d protein, mouse; D000071636:Protein Phosphatase 2C