miR-139-5p-PI3K/AKT/mTORC1 network has a role in supratentorial pediatric Low Grade Gliomas (pLGGs)

Abstract (miR-139-5p-PI3K/AKT/mTORC1 network has a role in supratentorial pediatric Low Grade Gliomas (pLGGs) Aim: Pediatric low-grade gliomas (pLGGs) are a heterogeneous group of brain tumours associated with a high overall survival: however, they are prone to recur and supratentorial lesions are difficult to resect, being associated with high percentage of disease recurrence. Our aim was to shed light on the biology of pLGGs. Methods: We performed microRNA profiling on 45 fresh-frozen grade I tumour samples of various histological classes, resected from patients aged ≤16 years. We identified 93 microRNAs specifically dysregulated in tumours as compared to non-neoplastic brain tissue. Enriched pathway analysis of the microRNAs signature revealed PI3K/AKT signaling as the first enriched oncogenic signaling. Although, activation of the PI3K/AKT pathway has been previously reported in these tumours, the activation mechanisms that are involved have not been investigated yet. Results: Among significantly down-regulated microRNAs in supratentorial pLGGs cohort the miR-139-5p was of interest since its targets include the gene encoding the PI3K’s (phosphatidylinositol 3-kinase) catalytic unit, PIK3CA. Thus, the role of miR-139-5p in regulating PI3K/AKT signaling has been investigated by the use of primary patients derived cells. In these models the overexpression of miR-139-5p inhibited pLGG cell proliferation and decreased the phosphorylation of PI3K target AKT and phosphorylated-p70 S6 kinase (p-p70 S6K), a hallmark of PI3K/AKT/mTORC1 signaling activation. The effect of miR-139-5p was mediated by PI3K inhibition, as suggested by the decrease in proliferation and phosphorylation of AKT and p70 S6K after treatment with the direct PI3K inhibitor LY294002. Conclusions: These findings provide the first evidence that down-regulation of miR-139-5p in supratentorial pLGG drives cell proliferation by derepressing PI3K/AKT signaling.