Abstract
Abstract Medulloblastoma (MB), the most prevalent brain malignancy in children, poses challenges in paediatric oncology due to its aggressiveness and potential for metastasis. Tailored treatment strategies are essential due to the impact of treatment-related toxicities and long-term side effects on children’s developing brains. This study aimed to identify therapeutic targets for paediatric MB and explore common biosignatures with glioblastoma multiforme (GBM), the most aggressive adult brain tumour. Total RNA and microRNAs (miRNAs) were extracted from eleven paediatric brain tissues (normal brain tissues, n=2; MB tumour tissue, n=8; pilocytic astrocytoma, n=1). High-throughput small-RNA sequencing (sRNA-seq) and transcriptomics were performed to identify the most deregulated miRNAs in paediatric MB tissue samples. Selected miRNAs, gene targets and encoded proteins were evaluated in vitro and ex vivo via real-time polymerase chain reaction (RT-qPCR), western blotting and immunohistochemistry (IHC). The sRNA-seq demonstrated that miR-383 and miR-206 were highly down regulated in MB samples suggesting their tumour suppressor properties. Bioinformatics analysis using miRSystem and TargetScan identified SV2B and CORO1C as their direct targets, respectively. Transcriptomics showed significant upregulation of SV2B and CORO1C in MB tissue samples. RT-qPCR analysis confirmed overexpression of SV2B and CORO1C within GBM cell lines and IHC depicted significant overexpression of SV2B and CORO1C proteins in paediatric MB and GBM patient cohorts (n=28) compared to their normal brain counterparts (n=32). Elevated CORO1C expression was also detected in adult MB (n=23) and GBM (n=73) tissue samples, when compared to normal brain tissue. Western blotting further verified the significant overexpression of CORO1C and SV2B within GBM cells, suggesting their role as potential oncoproteins. Collectively, our preliminary study proposes the clinical significance of miR-206 and miR-383 when overexpressed in the therapy of aggressive paediatric and adult brain malignancies.
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