Abstract

Meningioma is the most common intracranial tumour, accounting for one third of all primary brain and central nervous system (CNS) tumours. According to the World Health Organization (WHO), meningiomas are classified as grade I, II, and III based on the histological features of tumours, with higher grades associated with greater morbidity and mortality. In most cases, meningioma can be managed by surgery alone; however, adjuvant treatment may be required in case of recurrent or higher-grade tumours. To date, chemotherapy has proven ineffective in treating meningioma patients, highlighting the need to identify novel molecular biomarkers and therapeutic targets, establishing effective non- invasive treatments. The aim of this project is to elucidate microRNA (miRNA)- associated post-translational mechanisms involved in the regulation of Cyclin D1, which has been suggested as a potential prognostic biomarker for meningioma. By focusing on the analysis of specific miRNAs by comparing WHO I, II, and III meningioma tissues and matched blood samples, this study identified potential diagnostic biomarkers circulating in peripheral blood to support the discovery of early tumour recurrence. Moreover, determination of the factors responsible for driving deregulation of miRNA candidates may generate potential therapeutic targets. IV Overexpression of Cyclin D1 was found to correlate with downregulation of the miR-497~195 cluster via the GATA binding protein 4 (GATA-4), a zinc finger transcription factor upregulated in malignant meningioma. Studies in our cell culture model of meningioma demonstrated that high levels of GATA-4 in malignant meningioma cells augment cell viability by controlling the expression of the miR-497~195 cluster, increasing the expression of Cyclin D1, D2, D3, and E1. Consistently, the small-molecule inhibitor NSC140905 reduced GATA-4 activity in malignant meningioma KT21-MG1 cells, restoring miR-497~195 levels. This resulted in decreased cell viability, and reduction of Cyclin D1, D2, D3, and E1 expression. Furthermore, analysis of miR-497~195 in circulating exosomes, derived from higher-grade (grade II and III) meningioma patients, showed lower levels of the miR-497 compared to those of benign origin (grade I). In conclusion, these findings suggest that GATA-4 is a novel potential therapeutic target for malignant meningioma correlating with the miR-497~195 cluster. Moreover, analysis of circulating exosome cargo suggests miR-497 to be a potential non-invasive biomarker for higher-grade meningioma tumours.

Keywords

Meningioma, miRNA, Exosomes, Liquid biopsies, GATA-4

Document Type

Thesis

Publication Date

2020

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