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.
Highlights
Gliomas represent the most common brain tumors in children
These findings indicate that pediatric high-grade gliomas (pHGGs) are characterized by increased levels of activated Notch2 (NICD2), supporting our hypothesis that this Notch receptor plays a functional role in these tumors
In the present study we identified a microRNA-based mechanism that activates proliferative Notch2 signaling in pHGGs
Summary
Gliomas represent the most common brain tumors in children. Approximately 21% of all primary pediatric gliomas are high-grade tumors [1,2]. In light of the growing body of evidence pointing to microRNAs as major mediators of deregulated gene expression in tumors [20], including pHGGs [5], we hypothesized that the activation of Notch signaling in pHGGs might be related at least in part to under-expression of one or more microRNAs. Here we show that three microRNAs previously reported to be down-regulated in pHGGs [5] were found to target the 3 -UTR of Notch: miR-107, miR-181c and miR-29a-3p, and their re-expression in KNS42 cells produced substantial reductions in Notch protein levels and cell proliferation rates. We show that three microRNAs previously reported to be down-regulated in pHGGs [5] were found to target the 3 -UTR of Notch: miR-107, miR-181c and miR-29a-3p, and their re-expression in KNS42 cells produced substantial reductions in Notch protein levels and cell proliferation rates These findings reveal a novel network that controls pHGG cell growth and identify new molecular targets for more effective treatment of these devastating pediatric brain tumors
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