Abstract
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.
Highlights
Glioblastoma (GBM) is the most malignant primary brain tumor in adults with overall survival of 14-15 months [1,2]
In order to clarify the role of miR-370-3p in GBM, we analyzed its expression in 12 human GBM tissues and 27 GBM stem-like cells (GSCs) derived from GBM surgical specimens
CD73 was not found to be a direct target of miR-370-3p, its expression was reduced in TRIPZ-miR-370 compared to TRIPZ empty vector cells as assessed by flow cytometry (Figure 3D). These results suggest that miR-370-3p may indirectly modulate CD73 expression by directly regulating HIF1A expression as HIF1A binds to the NT5E promoter thereby activating CD73 expression [36,37]
Summary
Glioblastoma (GBM) is the most malignant primary brain tumor in adults with overall survival of 14-15 months [1,2]. At the opposite end of the size are the long non-coding RNAs (lncRNAs), which are a very heterogeneous group of transcripts that have been identified as essential players in gene regulation by different mechanisms [6]. MiRNAs and lncRNAs are the two most widely studied classes of ncRNAs. LncRNAs are RNAs with no functional protein-coding ability, associated with various biological processes such as epigenetic regulation, apoptosis, cell cycle, regulation of transcription and translation, cell growth, differentiation, and stem cell biology [7]. Studies so far suggest that many functional lncRNAs have the potential to act as oncogenes and/or tumor suppressors [9,11]. We showed a critical role for miR-370-3p in the regulation of GBM development, suggesting that this miRNA might act as a tumor-suppressor factor. Our study provides evidence of a potential therapeutic role of miR-370-3p in the treatment of GBM
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