Loss of miR-107, miR-181c and miR-29a-3p promote activation of Notch2 signaling in pediatric high-grade gliomas (pHGGs)

The mechanisms by which microRNAs control pediatric high-grade gliomas (pHGGs) haveyet to be fully elucidated. Our studies of patient-derived pHGG tissues and of the pHGG cell lineKNS42 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-repressingexpression of the Notch2 receptor (Notch2), a validated target of miR-107 and miR-181c and aputative target of miR-29a-3p. Inhibition (either pharmacologic or genetic) of Notch2 or re-expressionof the implicated microRNAs (all three combined but also individually) significantly reduced KNS42cell proliferation. These findings suggest that Notch2 pathway activation plays a critical role inpHGGs growth and reveal a direct epigenetic mechanism that controls Notch2 expression, whichcould potentially be targeted by novel forms of therapy for these childhood tumors characterized byhigh-morbidity and high-mortality.