Loss of miR-107, miR-181c and miR-29a-3p Promote Activation of Notch2 Signaling in Pediatric High-Grade Gliomas (pHGGs).
Giuseppina CatanzaroClaudia SabatoMichele RussoAlessandro RosaLuana AbballeZein Mersini BesharatAgnese PoEvelina MieleDiana BellaviaMartina ChiacchiariniMarco GessiGiovanna PeruzziMaddalena NapolitanoManila AntonelliAngela MastronuzziFelice GiangasperoFranco LocatelliIsabella ScrepantiAlessandra VaccaElisabetta FerrettiPublished in: International journal of molecular sciences (2017)
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.
Keyphrases
- cell proliferation
- high grade
- long non coding rna
- poor prognosis
- cell cycle
- long noncoding rna
- low grade
- pi k akt
- gene expression
- binding protein
- type diabetes
- dna methylation
- cell cycle arrest
- cancer therapy
- coronary artery disease
- drug delivery
- cardiovascular events
- single cell
- endoplasmic reticulum stress
- copy number
- case control