New role of osteopontin in DNA repair and impact on human glioblastoma radiosensitivity
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Aurélie Henry1, Marie-Julie Nokin1, Natacha Leroi2, François Lallemand2,3,4, Jérémy Lambert5, Nicolas Goffart5,6, Patrick Roncarati7, Elettra Bianchi7, Paul Peixoto1, Arnaud Blomme1, Andrei Turtoi1, Olivier Peulen1, Yvette Habraken8, Félix Scholtes9, Philippe Martinive3, Philippe Delvenne7, Bernard Rogister5, Vincent Castronovo1, Akeila Bellahcène1
1Metastasis Research Laboratory, GIGA Cancer, University of Liège, Liège, Belgium
2Biology and Tumor Development Laboratory, GIGA Cancer, University of Liège, Liège, Belgium
3Department of Radiology, University Hospital Liège, Liège, Belgium
4Cyclotron Research Center, University Hospital Liège, Liège, Belgium
5GIGA Neurosciences, University of Liège, Liège, Belgium
6Department of Neurosurgery, Brain Center Rudolf Magnus Institute of Neurosciences and the T&P Bohnenn Laboratory for Neuro-Oncology University Medical Center, Utrecht, The Netherlands
7Department of Pathology, University Hospital Liège, Liège, Belgium
8Virology and Immunology Laboratory, University of Liège, Liège, Belgium
9Department of Neurosurgery, University Hospital Liège, Liège, Belgium
Akeila Bellahcène, email: [email protected]
Keywords: osteopontin, glioblastoma, radioresistance, DNA damage repair, EGFRvIII
Received: June 16, 2016 Accepted: August 05, 2016 Published: August 22, 2016
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.
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