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) 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.