Abstract
Abstract High-grade gliomas (HGG) are the deadliest central nervous system tumour in children. Despite this, treatment options remain elusive, leaving children with a dismal prognosis. Histone H3.3 mutations, K27M and G34V/R have been identified as the two most common recurrent somatic mutations in paediatric HGG (pHGG). These mutations are present in 50% of pHGG compared to only 1% in adult gliomas. Our previous proteomic research on cell membrane protein through protein MS data analyses have identified different signatures of differentially expressed cell membrane proteins in H3-G34R/V mutated pHGG cells, in comparison to H3 wild type tumour cells in culture. Among these proteins we have identified flotillin-1, HMGB1 (High mobility group box 1) and aminopeptidase N. Flotillin-1 is associated with numerous malignancies and HMGB1 also functions as an oncogene and aminopeptidase N is a cell surface metalloprotease involved in tumour progression. We have now verified the expression and localisation of these cell surface proteins in H3 mutated and wild type tumour cells, in order to validate as targets for developing novel therapeutics. Expression and localisation of flotillin-1, HMGB1 and aminopeptidase N in H3.3 mutated pHGG cell lines in comparison to H3 wildtype glioma and control cells was analysed, using different protein expression assays including immunofluorescence microscopy and western blotting. Experimental analyses showed statistically significant differential protein expression and localisation of these proteins. Flotillin-1 had increased cell membrane localization in H3 mutated cells.HMGB1 expression was increased, while aminopeptidase N expression was decreased in the H3 mutated cells in comparison to wildtype pHGG. This new knowledge of the cell membrane proteomics of H3 mutated pHGG may help us utilise Flotillin-1, HMGB1 and aminopeptidase N, as potential therapeutic targets for these unique H3 mutated children’s brain tumours.
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