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

G. Catanzaro,C. Sabato,Michele Russo,A. Rosa,L. Abballe,Z. M. Besharat,A. Pò,E. Miele,D. Bellavia,M. Chiacchiarini,M. Gessi,G. Peruzzi,M. Napolitano,M. Antonelli,A. Mastronuzzi,F. Giangaspero,F. Locatelli,I. Screpanti,A. Vacca,E. Ferretti

Published 2017 in International Journal of Molecular Sciences

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.

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