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MicroRNA519d and microRNA4758 can identify gangliogliomas from dysembryoplastic neuroepithelial tumours and astrocytomas

2018; Impact Journals LLC; Volume: 9; Issue: 46 Linguagem: Inglês

10.18632/oncotarget.25563

1949-2553

Anika Bongaarts, Avanita S. Prabowo, Andrea Arena, Jasper J. Anink, Roy J. Reinten, Floor E. Jansen, Wim G.M. Spliet, Maria Thom, Roland Coras, Ingmar Blümcke, Katarzyna Kotulska, Sergiusz Jóźwiak, Wiesława Grajkowska, Figen Söylemezoğlu, José Pimentel, Antoinette Y. N. Schouten–van Meeteren, James D. Mills, Anand M. Iyer, Erwin A. van Vliet, Angelika Mühlebner, Eleonora Aronica,

Circular RNAs in diseases

// Anika Bongaarts 1, * , Avanita S. Prabowo 1, * , Andrea Arena 1, 2 , Jasper J. Anink 1 , Roy J. Reinten 1 , Floor E. Jansen 3 , Wim G.M. Spliet 4 , Maria Thom 5 , Roland Coras 6 , Ingmar Blümcke 6 , Katarzyna Kotulska 7 , Sergiusz Jozwiak 7, 8 , Wieslawa Grajkowska 9 , Figen Söylemezoğlu 10 , José Pimentel 11 , Antoinette Y.N. Schouten-van Meeteren 12 , James D. Mills 1 , Anand M. Iyer 1 , Erwin A. van Vliet 1 , Angelika Mühlebner 1, 13 and Eleonora Aronica 1, 14 1 Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands 2 Department of Biochemical Sciences, Sapienza University of Rome, Rome, Italy 3 Department of Pediatric Neurology, University Medical Center Utrecht, Utrecht, The Netherlands 4 Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands 5 Neuropathology Department, University College London, Institute of Neurology, London, UK 6 Department of Neuropathology, University Hospital Erlangen, Erlangen, Germany 7 Department of Neurology and Epileptology, Children's Memorial Health Institute, Warsaw, Poland 8 Department of Child Neurology, Medical University of Warsaw, Warsaw, Poland 9 Department of Pathology, Children's Memorial Health Institute, Warsaw, Poland 10 Department of Pathology, Faculty of Medicine, Hacettepe University, Ankara, Turkey 11 Department of Neurology, Hospital de Santa Maria, Lisbon, Portugal 12 Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands 13 Department of Pediatrics, Medical University of Vienna, Vienna, Austria 14 Stichting Epilepsie Instellingen Nederland, Heemstede, The Netherlands * These authors have contributed equally to this work Correspondence to: Eleonora Aronica, email: e.aronica@amc.uva.nl 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 ABSTRACT 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.