RESUMO
AIMS: Neurofibromatosis 1 (NF1) is an autosomal-dominant cancer predisposition syndrome caused by loss of function alterations involving the NF1 locus on chromosome 17. The most common brain tumours encountered in affected patients are low-grade gliomas (pilocytic astrocytomas), although high-grade gliomas are also observed at increased frequency. While bi-allelic NF1 loss characterizes these tumours, previous studies have suggested noncoding RNA molecules (microRNA, miR) may have important roles in dictating glioma biology. METHODS: To explore the contributions of miRs in NF1-associated gliomas, we analysed five high-grade gliomas (NF1-HGG) and five PAs (NF1-PA) using global microRNA profiling with NanoString-based microarrays followed by functional experiments with glioma cell lines. RESULTS: miR-10b-5p, miR-135b-5p, miR-196a-5p, miR-196b-5p, miR-1247-5p and miR-320a (adjusted P < 0.05) were increased> 3-fold in NF1-HGG relative to NF1-PA tumours. In addition, miR-378b and miR-1305 were decreased 6.8- and 6-fold, respectively, whereas miR-451a was increased 2.7-fold (adjusted P < 0.05) in NF1-PAs compared to non-neoplastic NF1 patient brain specimens (n = 2). As miR-10b-5p was the microRNA overexpressed the most in NF1-high-grade glioma compared to NF1-low-grade glioma (5.76 fold), we examined its levels in glioma cell lines. miR-10b-5p levels were highest in adult glioma cell lines and lowest in paediatric low-grade glioma lines (P = 0.02). miR-10b-5p knockdown resulted in decreased invasion in NF1-deficient LN229 high-grade glioma line, whereas its overexpression in the NF1-PA derived line (JHH-NF1-PA1) led to increased invasion. There was no change in cell growth (viability and proliferation). CONCLUSIONS: These proof-of-concept experiments support a role for microRNA regulation in NF1-glioma biology.