GATA-4, a potential novel therapeutic target for high-grade meningioma, regulates miR-497, a potential novel circulating biomarker for high-grade meningioma

Abstract

Background Meningiomas are the most common primary intracranial tumours. They are classified as grade I, II, and III based on their histopathological features. While most meningiomas can be managed by surgery alone, adjuvant treatment may be required in case of recurrent, or high-grade tumours. To date, chemotherapy has proven ineffective in meningioma patients, reinforcing the need for novel therapeutic targets and molecular biomarkers. Methods Using meningioma tissues and in vitro models, we investigated microRNA levels in meningioma samples of different grades, as well as their regulation. Based on this, we also investigated candidate miRNAs expression in serum, and their potential as biomarkers. Findings We found that miR-497~195 cluster expression in meningioma decreases with increasing malignancy grade, and that Cyclin D1 overexpression correlated with downregulation of the miR-497~195 cluster. GATA binding protein 4, a transcription factor upregulated in malignant meningioma, caused increased cell viability by controlling the expression of the miR-497~195 cluster, resulting in increased Cyclin D1 expression. Accordingly, GATA-4 inhibition via the small-molecule inhibitor NSC140905 restored miR-497~195 cluster expression, resulting in decreased viability, and Cyclin D1 downregulation. Analysis of the miR-497~195 cluster expression in serum exosomes derived from high-grade meningioma patients, revealed lower levels of miR-497 compared to those of benign origin. Interpretation Our data suggest that GATA-4 could be a novel potential therapeutic target, and miR-497 could serve as a potential non-invasive biomarker for high-grade meningioma.

The Role of MicroRNAs in Therapeutic Resistance of Malignant Primary Brain Tumors

“…Thus, miRNAs are one of the key factors in the development of malignant forms of brain tumors, both as drivers of malignant transformation and as a victim of the deregulation of cellular regulatory systems. The close relationship of miRNAs with MPBTs has led to the fact that they are currently being actively studied (Table 1; Grunder et al, 2011;Kliese et al, 2013;Asuthkar et al, 2014;Wang et al, 2015;Wei et al, 2015;Yu et al, 2016;Zheng et al, 2017;Xu et al, 2018;Xue et al, 2019;Hou et al, 2020;Muñoz-Hidalgo et al, 2020;Negroni et al, 2020;Song et al, 2020), including with the aim of creating diagnostic and therapeutic systems designed to increase the effectiveness of treatment of this disease.…”

Transcription Factors: The Fulcrum Between Cell Development and Carcinogenesis

“…Furthermore, the synthetic derivative of succinic acid NSC140905 [2-(1,3-benzodioxol-5-ylmethyl)butanedioic acid] was reported to bind to the DNA-binding domain of Gata4, thus blocking its transcriptional activity ( 252 ). Of note, treatment of meningioma cancer cells with NSC140905 decreased cancer cell viability but did not affect normal human meningeal cells in vitro ( 253 ). The potential of Sox decoy molecules, which target their DNA binding activity, has also been demonstrated to inhibit Sox18-induced genes in the COS-7 cell line ( 254 ).…”

The Emerging Role of Non-Coding RNAs in Pituitary Gland Tumors and Meningioma

“…In fact, the effect of GATA binding protein 4 in enhancing the viability of meningioma cells is exerted through the regulation of expression of this miRNA cluster, which finally results in enhancement of Cyclin D1 level. Finally, serum exosome levels of miR-497 are lower in patients with high-grade meningioma compared to those with benign lesions [ 67 ].…”