Authors: Bongaarts A., Prabowo A.S., Arena A., Anink J.J., Reinten R.J., Jansen F.E., Spliet W.G.M., Thom M., Coras R., Blümcke I., Kotulska K., Jozwiak S., Grajkowska W., Söylemezoglu F., Pimentel J., Schouten-van Meeteren A.Y.N., Mills J.D., Iyer A.M., van Vliet E.A., Mühlebner A., Aronica E.

Oncotarget 2018 Jun 15;9(46):28103-28115. doi: 10.18632/oncotarget.25563

Abstract

Glioneuronal tumours, including gangliogliomas and dysembryoplasticneuroepithelialtumours, 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), dysembryoplasticneuroepithelialtumours (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 dysembryoplasticneuroepithelialtumours and other low and high grade gliomas and may lead to more targeted therapy.