title: New role of osteopontin in DNA repair and impact on human glioblastoma radiosensitivity.
abstract: Glioblastoma (GBM) represents the most aggressive and common solid human brain tumor. We have recently demonstrated the importance of osteopontin (OPN) in the acquisition/maintenance of stemness characters and tumorigenicity of glioma initiating cells. Consultation of publicly available TCGA database indicated that high OPN expression correlated with poor survival in GBM patients. In this study, we explored the role of OPN in GBM radioresistance using an OPN-depletion strategy in U87-MG, U87-MG vIII and U251-MG human GBM cell lines. Clonogenic experiments showed that OPN-depleted GBM cells were sensitized to irradiation. In comet assays, these cells displayed higher amounts of unrepaired DNA fragments post-irradiation when compared to control. We next evaluated the phosphorylation of key markers of DNA double-strand break repair pathway. Activating phosphorylation of H2AX, ATM and 53BP1 was significantly decreased in OPN-deficient cells. The addition of recombinant OPN prior to irradiation rescued phospho-H2AX foci formation thus establishing a new link between DNA repair and OPN expression in GBM cells. Finally, OPN knockdown improved mice survival and induced a significant reduction of heterotopic human GBM xenograft when combined with radiotherapy. This study reveals a new function of OPN in DNA damage repair process post-irradiation thus further confirming its major role in GBM aggressive disease.
authors: Metastasis Research Laboratory, GIGA Cancer, University of Liège, Liège, Belgium.
authors: Aurélie
authors: A
authors: Henry
authors: Metastasis Research Laboratory, GIGA Cancer, University of Liège, Liège, Belgium.
authors: Marie-Julie
authors: MJ
authors: Nokin
authors: Biology and Tumor Development Laboratory, GIGA Cancer, University of Liège, Liège, Belgium.
authors: Natacha
authors: N
authors: Leroi
authors: Biology and Tumor Development Laboratory, GIGA Cancer, University of Liège, Liège, Belgium.|Department of Radiology, University Hospital Liège, Liège, Belgium.|Cyclotron Research Center, University Hospital Liège, Liège, Belgium.
authors: François
authors: F
authors: Lallemand
authors: GIGA Neurosciences, University of Liège, Liège, Belgium.
authors: Jérémy
authors: J
authors: Lambert
authors: GIGA Neurosciences, University of Liège, Liège, Belgium.|Department of Neurosurgery, Brain Center Rudolf Magnus Institute of Neurosciences and the T&P Bohnenn Laboratory for Neuro-Oncology University Medical Center, Utrecht, The Netherlands.
authors: Nicolas
authors: N
authors: Goffart
authors: Department of Pathology, University Hospital Liège, Liège, Belgium.
authors: Patrick
authors: P
authors: Roncarati
authors: Department of Pathology, University Hospital Liège, Liège, Belgium.
authors: Elettra
authors: E
authors: Bianchi
authors: Metastasis Research Laboratory, GIGA Cancer, University of Liège, Liège, Belgium.
authors: Paul
authors: P
authors: Peixoto
authors: Metastasis Research Laboratory, GIGA Cancer, University of Liège, Liège, Belgium.
authors: Arnaud
authors: A
authors: Blomme
authors: Metastasis Research Laboratory, GIGA Cancer, University of Liège, Liège, Belgium.
authors: Andrei
authors: A
authors: Turtoi
authors: Metastasis Research Laboratory, GIGA Cancer, University of Liège, Liège, Belgium.
authors: Olivier
authors: O
authors: Peulen
authors: Virology and Immunology Laboratory, University of Liège, Liège, Belgium.
authors: Yvette
authors: Y
authors: Habraken
authors: Department of Neurosurgery, University Hospital Liège, Liège, Belgium.
authors: Félix
authors: F
authors: Scholtes
authors: Department of Radiology, University Hospital Liège, Liège, Belgium.
authors: Philippe
authors: P
authors: Martinive
authors: Department of Pathology, University Hospital Liège, Liège, Belgium.
authors: Philippe
authors: P
authors: Delvenne
authors: GIGA Neurosciences, University of Liège, Liège, Belgium.
authors: Bernard
authors: B
authors: Rogister
authors: Metastasis Research Laboratory, GIGA Cancer, University of Liège, Liège, Belgium.
authors: Vincent
authors: V
authors: Castronovo
authors: Metastasis Research Laboratory, GIGA Cancer, University of Liège, Liège, Belgium.
authors: Akeila
authors: A
authors: Bellahcène
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000532:radiotherapy; D045744:Cell Line, Tumor; D020552:Comet Assay; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D005260:Female; D020868:Gene Silencing; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000532:radiotherapy; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D011836:Radiation Tolerance; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D011994:Recombinant Proteins; C506895:SPP1 protein, human; D053495:Osteopontin
keywords: DNA damage repair; EGFRvIII; glioblastoma; osteopontin; radioresistance