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

Valentina Lulli, Mariachiara Buccarelli, Ramona Ilari, Giorgia Castellani, Chiara De Dominicis, Alessandra Di Giamberardino, Quintino Giorgio D Alessandris, Stefano Giannetti, Maurizio Martini, Vittorio Stumpo, Alessandra Boe, Gabriele De Luca, Mauro Biffoni, Giovanna Marziali, Roberto Pallini, Lucia Ricci-Vitiani, Valentina Lulli, Mariachiara Buccarelli, Ramona Ilari, Giorgia Castellani, Chiara De Dominicis, Alessandra Di Giamberardino, Quintino Giorgio D Alessandris, Stefano Giannetti, Maurizio Martini, Vittorio Stumpo, Alessandra Boe, Gabriele De Luca, Mauro Biffoni, Giovanna Marziali, Roberto Pallini, Lucia Ricci-Vitiani

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.

Keywords: HIF1A; HMGA2; MiR-370-3p; glioblastoma; glioblastoma stem-like cells; lncRNA NEAT1.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
miR-370-3p is down-regulated in Glioblastoma (GBM) tissues and Glioblastoma Stem-like Cell (GSC) lines and its restoration reduces cell growth, migration and clonogenic abilities of GSCs. (A) Real time RT-PCR analysis of miR-370-3p expression performed on normal brain tissue samples (NB, n = 12), GBM tissues (GBM, n = 12), NSCs (n = 5) and GSCs (n = 27). Samples were run in duplicate and normalized with Glyceraldehyde-3-Phosphate Dehydrodenase (GAPDH). * p < 0.05; ** p < 0.01; *** p < 0.001. (B) Real time PCR analysis of miR-370-3p expression in GSC#1, #61, #83 and #163 transduced with either TRIPZ or TRIPZ-miR-370 inducible vectors. (C) Growth curves of GSCs transduced with either TRIPZ or TRIPZ-miR-370 vector. Points and range lines at each day represent mean and SD of at least two independent experiments in triplicate. Two-way analysis of variance for repeated measures was performed on the whole set of data. (D) Analysis of migration efficiency in GSCs transduced with TRIPZ-miR-370 vector 48 h after induction. Values are reported as percentage relative to control vector and shown as mean ± SD from two independent experiments in triplicate. (E) Analysis of efficiency in colony formation of GSCs after transduction with TRIPZ-miR-370 vector. Percent colony number values from two independent experiments in triplicate were calculated over the correspondent empty vector and are shown as mean ± SD for each GSC line.
Figure 2
Figure 2
Restoration of miR-370 inhibits tumor growth in orthotopic xenograft mouse models. Fluorescence microscopy of mouse brain grafted onto the right striatum with GSC#1 cells. Upper panel, Photomontage of coronal section in a TRIPZ xenograft (A) showing the injection area (B) and tumor spreading to the subventricular zone of the contralateral hemisphere (C). The arrows point to tumor cells. Lower panel, Photomontage of coronal section in a TRIPZ-miR-370 xenograft (F). A few tumor cells with cell debris are found in the injection area (G). There is no contralateral spreading of tumor cells (H). Scale bars. A and F, 1 mm; B and G, 135 μm; C and H, 150 μm. Ki67 immunostaining showing positive nuclei of proliferating cells (red) in a TRIPZ xenograft (D–E) and in a TRIPZ-miR-370 xenograft (I–J). Scale bars. D and I, 90μm; E and J, 70 μm.
Figure 3
Figure 3
Effect of miR-370 restoration in GSCs. (A) Pathway enrichment analysis examined by GSEA software of highly modulated genes (≥2 fold both up and down) in GSC#1 transduced with TRIPZ-miR-370 vs TRIPZ empty vector. (B) RT-PCR analysis performed on GSC#1 and GSC#83 transduced with TRIPZ or TRIPZ-miR-370 for HMGA2 (left panel) and Hypoxia-inducible factor (HIF) 1A expression (right panel). * p < 0.05; ** p < 0.01. (C) Predicted binding site of miR-370-3p in the HIF1A 3′UTR sequence (left panel). Dual-luciferase reporter assay of pGL3 vectors containing the HIF1A 3′UTR or HIF1A mutant (mut), co-transfected in 293T cells with hsa-miR-370-3p-mimic or control mimic RNA (ctrl). ** p < 0.01. Histograms show normalized mean values of the relative luciferase activity. Error bars represent the mean ± SD (n = 4) (right panel) (D) FACS analysis of NT5E/CD73 on GSC#1 and GSC#83 transduced with TRIPZ empty vector and TRIPZ-miR-370 after doxycycline induction.
Figure 4
Figure 4
Nuclear Enriched Abundant Transcript 1 (NEAT1) is a target of miR-370-3p and its expression in GBM tissues and GSC lines is inversely correlated with miR-370-3p. (A) Binding sites between miR-370-3p and NEAT1 at +1500 (left panel) and at +6500 (right panel) nucleotides of RNA sequence. (B) Dual-luciferase reporter assays in 293T cells co-transfected with reporter vectors containing the wild type (wt) or the mutated (mut) NEAT1(1500) (left panel) or NEAT1(6500) (right panel) sequences and miR-370-3p-mimic or control mimic RNA (ctrl). Bar charts show normalized mean values of the relative luciferase activity. Error bars represent the mean ± SD (n = 4) (student t-test: ** p < 0.01; *** p < 0.001. (C) RT-PCR analysis performed on normal brain samples (NB, n = 12), GBM tissues (GBM, n = 12), NSCs (n = 5) and GSCs (n = 27). Samples were run in duplicate and normalized with GAPDH. * p < 0.05; ** p < 0.01; *** p < 0.001. (D) Correlation analysis between miR-370-3p and NEAT1 expression levels in GBM tissues and (E) in GSC lines.
Figure 5
Figure 5
Correlation between miR-370-3p and NEAT1 expression and overall survival (OS) of GBM patients. (A) Kaplan–Meier curve for OS in our cohort of GBM patients stratified for low miR-370-3p expression (<the median value) vs high miR-370-3p expression (>the median value). The last group was not associated to a better outcome (n = 27, p = 0.09, Hazard Ratio (HR) 0.4778, 95% CI from 0.2029 to 1.1253). (B) Kaplan–Meier curve for OS in our cohort of GBM patients stratified for low NEAT1 expression (<the median value) vs. high NEAT1 expression (>the median value). The last group was significantly associated to a worse outcome (n = 27, p = 0.035, HR 2.7980, 95% CI from 1.0754 to 7.2804). (C) Kaplan–Meier curve for OS in GBM The Cancer Genome Atlas (TCGA) patients stratified for low miR-370-3p/ high NEAT1 vs. high miR-370-3p/ low NEAT1. The last group was significantly associated to a better outcome (n = 153, p = 0.0215, HR 0.6855, 95% CI from 0.4968 to 0.9458). (D) Kaplan–Meier curve for OS in GBM TCGA patients stratified for low miR-370-3p/high NEAT1/high HIF1A vs high miR-370-3p/low NEAT1/low HIF1A (n = 47, p = 0.4400, HR 0.7927, 95% CI from 0.4395 to 1.4296).
Figure 6
Figure 6
NEAT1 knockdown impairs GSC tumorigenicity. (A) Real time PCR analysis for NEAT1 on GSC#1 and GSC#83 miR-370-3p transduced lines confirmed the down-regulation of the lncRNA. ** p < 0.01; *** p < 0.001. (B) Real time PCR for NEAT1, miR-370-3p, HIF1A and HMGA2 on GSC#1 (left panel) and GSC#83 (right panel) transduced with short hairpin (sh)NEAT1 or its no target control lentiviral vector (shNTC). * p < 0.05; ** p < 0.01. (C) Growth curves, (D) analysis of efficiency in colony formation and analysis of migration efficiency in GSC#1 (left panel) and GSC#83 (right panel) transduced with shNEAT1 or shNTC. Values shown are mean ± SD from two independent experiments in triplicate. ** p < 0.01; *** p < 0.001.
Figure 7
Figure 7
Schematic drawing of miR-370-3p regulation of HMGA2-HIF1A-NEAT1 interplay and effect on GBM tumorigenesis. Representation of the mechanism proposed in the present study. miR-370-3p down-regulation leads to increased expression of the lncRNA NEAT1, the Epithelial to Mesenchymal Transition (EMT)-inducer HMGA2, the master transcriptional regulator HIF1A, which in turn activates NT5E expression. NEAT1 inhibits the expression of miR-370-3p, promoting the up-regulation of HMGA2 and HIF1A and contributing to GBM progression.

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