Int. J. Mol. Sci. 2017, 18(12), 2742; https://doi.org/10.3390/ijms18122742
Loss of miR-107, miR-181c and miR-29a-3p Promote Activation of Notch2 Signaling in Pediatric High-Grade Gliomas (pHGGs)
Giuseppina Catanzaro 1,†, Claudia Sabato 2,3,†, Michele Russo 2, Alessandro Rosa 3,4
, Luana Abballe 1, Zein Mersini Besharat 1, Agnese Po 2, Evelina Miele 5, Diana Bellavia 2, Martina Chiacchiarini 2,3, Marco Gessi 6, Giovanna Peruzzi 3, Maddalena Napolitano 2, Manila Antonelli 7, Angela Mastronuzzi 5, Felice Giangaspero 7,8, Franco Locatelli 5,9, Isabella Screpanti 2,3,10, Alessandra Vacca 1,† and Elisabetta Ferretti 1,8,†,*
, Luana Abballe 1, Zein Mersini Besharat 1, Agnese Po 2, Evelina Miele 5, Diana Bellavia 2, Martina Chiacchiarini 2,3, Marco Gessi 6, Giovanna Peruzzi 3, Maddalena Napolitano 2, Manila Antonelli 7, Angela Mastronuzzi 5, Felice Giangaspero 7,8, Franco Locatelli 5,9, Isabella Screpanti 2,3,10, Alessandra Vacca 1,† and Elisabetta Ferretti 1,8,†,*
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 [email protected], 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)
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-TextKeywords:
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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