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Int. J. Mol. Sci. 2017, 18(12), 2742; doi:10.3390/ijms18122742

Loss of miR-107, miR-181c and miR-29a-3p Promote Activation of Notch2 Signaling in Pediatric High-Grade Gliomas (pHGGs)

1
Department of Experimental Medicine, Sapienza University, Viale Regina Elena, 291, 00161 Rome, Italy
2
Department of Molecular Medicine, Sapienza University, 00161 Rome, Italy
3
Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia, 00161 Rome, Italy
4
Department of Biology and Biotechnology “Charles Darwin”, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
5
Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children’s Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, 00165 Rome, Italy
6
Department of Histopathology, Fondazione Policlinico Universitario “A. Gemelli”, Università Cattolica Sacro cuore, Largo A. Gemelli 8, 00168 Rome, Italy
7
Department of Radiological, Oncological and Pathological Science, Sapienza University, 00161 Rome, Italy
8
Istituto di Ricovero e Cura a Carattere Scientifico Neuromed, Pozzilli, 86077 Isernia, Italy
9
Department of Pediatrics, University of Pavia, 27100 Pavia, Italy
10
Institute Pasteur-Foundation Cenci Bolognetti, Sapienza University, 00161 Rome, Italy
These authors contributed equally to the manuscript.
*
Author to whom correspondence should be addressed.
Received: 30 November 2017 / Revised: 11 December 2017 / Accepted: 13 December 2017 / Published: 17 December 2017
(This article belongs to the Special Issue Glioma Cell Invasion)
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Abstract

The mechanisms by which microRNAs control pediatric high-grade gliomas (pHGGs) have yet to be fully elucidated. Our studies of patient-derived pHGG tissues and of the pHGG cell line KNS42 revealed down-regulation in these tumors of three microRNAs, specifically miR-107, miR-181c, and miR-29a-3p. This down-regulation increases the proliferation of KNS42 cells by de-repressing expression of the Notch2 receptor (Notch2), a validated target of miR-107 and miR-181c and a putative target of miR-29a-3p. Inhibition (either pharmacologic or genetic) of Notch2 or re-expression of the implicated microRNAs (all three combined but also individually) significantly reduced KNS42 cell proliferation. These findings suggest that Notch2 pathway activation plays a critical role in pHGGs growth and reveal a direct epigenetic mechanism that controls Notch2 expression, which could potentially be targeted by novel forms of therapy for these childhood tumors characterized by high-morbidity and high-mortality. View Full-Text
Keywords: pediatric high-grade gliomas; Notch2 signaling; microRNAs; miR-107; miR-181c; miR-29a-3p; cell proliferation pediatric high-grade gliomas; Notch2 signaling; microRNAs; miR-107; miR-181c; miR-29a-3p; cell proliferation
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Catanzaro, G.; Sabato, C.; Russo, M.; Rosa, A.; Abballe, L.; Besharat, Z.M.; Po, A.; Miele, E.; Bellavia, D.; Chiacchiarini, M.; Gessi, M.; Peruzzi, G.; Napolitano, M.; Antonelli, M.; Mastronuzzi, A.; Giangaspero, F.; Locatelli, F.; Screpanti, I.; Vacca, A.; Ferretti, E. Loss of miR-107, miR-181c and miR-29a-3p Promote Activation of Notch2 Signaling in Pediatric High-Grade Gliomas (pHGGs). Int. J. Mol. Sci. 2017, 18, 2742.

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