The WIP1 oncogene promotes progression and invasion of aggressive medulloblastoma variants

• Type of Material: Article
• Authors: Meghan C. Buss, Aflac Cancer and Blood Disorders Center; Marc Remke, University of Toronto; Juhyun Lee, Aflac Cancer and Blood Disorders Center; Khanjan Gandhi, Emory University; Matthew Schniederjan, Emory University; Marcel Kool, Heidelberg University; Paul A. Northcott, Heidelberg University; Stefan M. Pfister, Heidelberg University; Michael D. Taylor, University of Toronto; Robert Castellino, Emory University
• Language: English
• Date: 2015-02-26
• Publisher: Nature Publishing Group
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015 Macmillan Publishers Limited.
• Final Published Version (URL): http://dx.doi.org/10.1038/onc.2014.37
• Title of Journal or Parent Work: Oncogene
• ISSN: 0950-9232
• Volume: 34
• Issue: 9
• Start Page: 1126
• End Page: 1140
• Grant/Funding Information: This work was supported by grants from the NIH (1R01CA172392–01, RCC; CA159859, MD Taylor), St Baldrick’s Foundation (RCC), CURE Childhood Cancer Foundation (RCC), Southeastern Brain Tumor Foundation (RCC), the Emory Egleston Children’s Research Center (RCC) and the Dr Mildred-Scheel Foundation (MR).; Research reported in this publication was supported in part by the NIH/NCI under award number P30CA138292.
• Keywords: ACTIVATION; P53 FUNCTION; PATHWAY; Biochemistry & Molecular Biology; Oncology; PPM1D; Science & Technology; PHOSPHATASE; MULTICENTER TRIAL; CANCER; Genetics & Heredity; Cell Biology; Life Sciences & Biomedicine; CHK2 KINASE; CHEMOKINE RECEPTOR CXCR4; DNA-DAMAGE
• Research Categories: Biology, Cell; Health Sciences, Oncology; Biology, Genetics

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 highexpressing 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.