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GFAPδ/GFAPα ratio directs astrocytoma gene expression towards a more malignant profile

2017; Impact Journals LLC; Volume: 8; Issue: 50 Linguagem: Inglês

10.18632/oncotarget.21540

1949-2553

Oscar M. J. A. Stassen, Emma J. van Bodegraven, Fabrizio Giuliani, Martina Moeton, Regina Kanski, Jacqueline A. Sluijs, Miriam E. van Strien, Willem Kamphuis, Pierre A. Robe, Elly M. Hol,

Neurogenesis and neuroplasticity mechanisms

// Oscar M.J.A. Stassen 1, 2, * , Emma J. van Bodegraven 3, * , Fabrizio Giuliani 4 , Martina Moeton 1 , Regina Kanski 1 , Jacqueline A. Sluijs 3 , Miriam E. van Strien 3 , Willem Kamphuis 1 , Pierre A.J. Robe 4 and Elly M. Hol 1, 3, 5 1 Netherlands Institute for Neuroscience, an Institute of The Royal Netherlands Academy of Arts and Sciences, 1105 BA Amsterdam, The Netherlands 2 Soft Tissue Engineering and Mechanobiology, Eindhoven University of Technology, 5612 AZ Eindhoven, The Netherlands 3 Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands 4 Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands 5 Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, 1098 XH Amsterdam, The Netherlands * These authors have contributed equally to this work Correspondence to: Elly M. Hol, email: e.m.hol-2@umcutrecht.nl Keywords: GFAP-isoforms, astrocytoma, transcriptomics, glioma, intermediate filaments Received: April 07, 2017 Accepted: July 25, 2017 Published: October 04, 2017 ABSTRACT Astrocytomas are the most common malignant brain tumours and are to date incurable. It is unclear how astrocytomas progress into higher malignant grades. The intermediate filament cytoskeleton is emerging as an important regulator of malignancy in several tumours. The majority of the astrocytomas express the intermediate filament protein Glial Fibrillary Acidic Protein (GFAP). Several GFAP splice variants have been identified and the main variants expressed in human astrocytoma are the GFAP α and GFAP δ isoforms. Here we show a significant downregulation of GFAP α in grade IV astrocytoma compared to grade II and III, resulting in an increased GFAPδ/ α ratio. Mimicking this increase in GFAPδ/α ratio in astrocytoma cell lines and comparing the subsequent transcriptomic changes with the changes in the patient tumours, we have identified a set of GFAPδ/α ratio-regulated high-malignant and low-malignant genes. These genes are involved in cell proliferation and protein phosphorylation, and their expression correlated with patient survival. We additionally show that changing the ratio of GFAPδ/α , by targeting GFAP expression, affected expression of high-malignant genes. Our data imply that regulating GFAP expression and splicing are novel therapeutic targets that need to be considered as a treatment for astrocytoma.