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Open AccessArticle

Mir-370-3p Impairs Glioblastoma Stem-Like Cell Malignancy Regulating a Complex Interplay between HMGA2/HIF1A and the Oncogenic Long Non-Coding RNA (lncRNA) NEAT1

1
Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy
2
Department of Neuroscience, Institute of Neurosurgery, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS; 00168 Rome, Italy
3
Department of Neuroscience, Institute of Anatomy, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
4
Department of Health Science and Public Health, Institute of Pathology, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
5
Core Facilities, Istituto Superiore di Sanità, 00161 Rome, Italy
*
Authors to whom correspondence should be addressed.
These authors equally contributed to the manuscript.
These two authors shared senior authorship.
Int. J. Mol. Sci. 2020, 21(10), 3610; https://doi.org/10.3390/ijms21103610
Received: 8 April 2020 / Revised: 15 May 2020 / Accepted: 18 May 2020 / Published: 20 May 2020
(This article belongs to the Special Issue The Plentiful Roles of RNA in Glioblastoma)
Glioblastoma (GBM) is the most aggressive and prevalent form of a human brain tumor in adults. Several data have demonstrated the implication of microRNAs (miRNAs) in tumorigenicity of GBM stem-like cells (GSCs). The regulatory functions of miRNAs in GSCs have emerged as potential therapeutic candidates for glioma treatment. The current study aimed at investigating the function of miR-370-3p in glioma progression, as aberrant expression of miR-370-3p, is involved in various human cancers, including glioma. Analyzing our collection of GBM samples and patient-derived GSC lines, we found the expression of miR-370-3p significantly downregulated compared to normal brain tissues and normal neural stem cells. Restoration of miR-370-3p expression in GSCs significantly decreased proliferation, migration, and clonogenic abilities of GSCs, in vitro, and tumor growth in vivo. Gene expression analysis performed on miR-370-3p transduced GSCs, identified several transcripts involved in Epithelial to Mesenchymal Transition (EMT), and Hypoxia signaling pathways. Among the genes downregulated by the restored expression of miR-370-3p, we found the EMT-inducer high-mobility group AT-hook 2 (HMGA2), the master transcriptional regulator of the adaptive response to hypoxia, Hypoxia-inducible factor (HIF)1A, and the long non-coding RNAs (lncRNAs) Nuclear Enriched Abundant Transcript (NEAT)1. NEAT1 acts as an oncogene in a series of human cancers including gliomas, where it is regulated by the Epidermal Growth Factor Receptor (EGFR) pathways, and contributes to tumor growth and invasion. Noteworthy, the expression levels of miR-370-3p and NEAT1 were inversely related in both GBM tumor specimens and GSCs, and a dual-luciferase reporter assay proved the direct binding between miR-370-3p and the lncRNAs NEAT1. Our results identify a critical role of miR-370-3p in the regulation of GBM development, indicating that miR-370-3p acts as a tumor-suppressor factor inhibiting glioma cell growth, migration and invasion by targeting the lncRNAs NEAT1, HMGA2, and HIF1A, thus, providing a potential candidate for GBM patient treatment. View Full-Text
Keywords: MiR-370-3p; lncRNA NEAT1; HMGA2; HIF1A; glioblastoma; glioblastoma stem-like cells MiR-370-3p; lncRNA NEAT1; HMGA2; HIF1A; glioblastoma; glioblastoma stem-like cells
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Lulli, V.; Buccarelli, M.; Ilari, R.; Castellani, G.; De Dominicis, C.; Di Giamberardino, A.; D′Alessandris, Q.G.; Giannetti, S.; Martini, M.; Stumpo, V.; Boe, A.; De Luca, G.; Biffoni, M.; Marziali, G.; Pallini, R.; Ricci-Vitiani, L. Mir-370-3p Impairs Glioblastoma Stem-Like Cell Malignancy Regulating a Complex Interplay between HMGA2/HIF1A and the Oncogenic Long Non-Coding RNA (lncRNA) NEAT1. Int. J. Mol. Sci. 2020, 21, 3610.

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