MicroRNA519d and microRNA4758 can identify gangliogliomas from dysembryoplastic neuroepithelial tumours and astrocytomas
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Anika Bongaarts1,*, Avanita S. Prabowo1,*, Andrea Arena1,2, Jasper J. Anink1, Roy J. Reinten1, Floor E. Jansen3, Wim G.M. Spliet4, Maria Thom5, Roland Coras6, Ingmar Blümcke6, Katarzyna Kotulska7, Sergiusz Jozwiak7,8, Wieslawa Grajkowska9, Figen Söylemezoğlu10, José Pimentel11, Antoinette Y.N. Schouten-van Meeteren12, James D. Mills1, Anand M. Iyer1, Erwin A. van Vliet1, Angelika Mühlebner1,13 and Eleonora Aronica1,14
1Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
2Department of Biochemical Sciences, Sapienza University of Rome, Rome, Italy
3Department of Pediatric Neurology, University Medical Center Utrecht, Utrecht, The Netherlands
4Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
5Neuropathology Department, University College London, Institute of Neurology, London, UK
6Department of Neuropathology, University Hospital Erlangen, Erlangen, Germany
7Department of Neurology and Epileptology, Children’s Memorial Health Institute, Warsaw, Poland
8Department of Child Neurology, Medical University of Warsaw, Warsaw, Poland
9Department of Pathology, Children’s Memorial Health Institute, Warsaw, Poland
10Department of Pathology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
11Department of Neurology, Hospital de Santa Maria, Lisbon, Portugal
12Department of Pediatric Oncology, Emma Children’s Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
13Department of Pediatrics, Medical University of Vienna, Vienna, Austria
14Stichting Epilepsie Instellingen Nederland, Heemstede, The Netherlands
*These authors have contributed equally to this work
Eleonora Aronica, email: [email protected]
Keywords: low-grade epilepsy-associated brain tumours, epilepsy, glioneuronal tumour, ganglioglioma, dysembryoplastic neuroepithelial tumour
Received: March 14, 2018 Accepted: May 19, 2018 Published: June 15, 2018
Glioneuronal tumours, including gangliogliomas and dysembryoplastic neuroepithelial tumours, represent the most common low-grade epilepsy-associated brain tumours and are a well-recognized cause of intractable focal epilepsy in children and young adults. Classification is predominantly based on histological features, which is difficult due to the broad histological spectrum of these tumours. The aim of the present study was to find molecular markers that can be used to identify entities within the histopathology spectrum of glioneuronal tumours. The focus of this study was on microRNAs (miRNAs). miRNAs are important post-transcriptional regulators of gene expression and are involved in the pathogenesis of different neurological diseases and oncogenesis. Using a miRNA array, miR-519d and miR-4758 were found to be upregulated in gangliogliomas (n=26) compared to control cortex (n=17), peritumoural tissue (n=7), dysembryoplastic neuroepithelial tumours (n=9) and astrocytomas (grade I-IV; subependymal giant cell astrocytomas, n=10; pilocytic astrocytoma, n=15; diffuse astrocytoma grade II, n=10; grade III, n=14 and glioblastoma n=15). Furthermore, the PI3K/AKT3/P21 pathway, which is predicated to be targeted by miR-519d and miR-4758, was deregulated in gangliogliomas. Functionally, overexpression of miR-519d in an astrocytic cell line resulted in a downregulation of CDKN1A (P21) and an increase in cell proliferation, whereas co-transfection with miR-4758 counteracted this effect. These results suggest that miR-519d and miR-4758 might work in concert as regulators of the cell cycle in low grade gliomas. Furthermore, these miRNAs could be used to distinguish gangliogliomas from dysembryoplastic neuroepithelial tumours and other low and high grade gliomas and may lead to more targeted therapy.
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