To evaluate the prognostic performance of the 13 miRNAs differentially expressed in grade II as compared with grade III+IV gliomas by RT-qPCR, we used the TCGA glioma datasets. This analysis demonstrated an association between increased expression and GBM prognosis for four miRNAs: miR155, miR-21, miR-210, and miR-22. Interestingly, these miRNAs belong to the subgroup of 9 miRNAs differentiating grade II gliomas from grade III+IV tumours in the Venn diagram generated by the analysis of our microarray data, further supporting their biological relevance. The examination of grade III tumours from the LGG dataset identified three miRNAs able to predict patients’ survival. Increased miR-155 expression was associated with worse OS in both grade III and grade IV gliomas. Whereas, increased miR-383 expression was associated with a lower risk of death only in grade III tumours. miR-1296 higher expression levels were also found associated with better prognosis in grade III gliomas but no information were available about its prognostic correlation with GBMs, since it was not included on the Agilent platform used to analyze the GBM dataset. As shown in Table S7, the 6 miRNAs associated with prognosis in this study are involved in all steps of cancer development and progression. We focused our attention on miR-21 and miR-210 because they were the only miRNAs associated with survival in both univariable and multivariable analyses in the GBM dataset and play a pivotal role in hypoxia-related pathways. Indeed, the main histopathological characteristics distinguishing GBMs from lower grade astrocytomas are the presence of foci of necrosis surrounded by hypercellular regions, and microvascular hyperplasia that are all hallmarks of hypoxia. This biological phenomenon has been related to aggressiveness and infiltrative behaviour in a wide variety of solid tumours. In GBM, gene expression profiles on microdissected cellular zones surrounding necrotic foci have revealed up regulation of HIF-1a, one of hypoxia-inducible factors mediating cancer cell adaptation to a hypoxic tumour environment. Overexpression of miR-21 in DU145 cells increases the expression of HIF-1a and VEGF and promotes tumor angiogenesis. Interestingly, Hermansen et al demonstrated by ISH analysis miR-21 expression in glioma and endothelial cells within the tumor, whereas no expression was detected in non-neoplastic blood vessels. These results are consistent with the hypothesis that miR-21 increased expression is related to tumor angiogenesis in gliomas. On the other side, miR-210 is ABT-263 robustly induced by hypoxia in many cell lines through HIF-1a. This activation determines downregulation of a number of genes which promote cancer cell survival and adaptation to adverse microenvironment, leading to the development of a more resistant and aggressive cell subpopulations. The downregulation of COX10 produces repression of electron transport chain to decrease oxygen-demand, and enhances anaerobic production of ATP via glicolysis enabling survival to hypoxic insults. Upregulation of miR-210 also causes repression of c-Myc inhibitor, MNT, promoting cell cycle and growth. It also contributes to maintenance of high HIF-1a levels during hypoxia, by suppressing of ISCU, SDHS, NUDFA4 proteins, in a feed-forward loop which sustains HIF-1a and its triggered processes. In addition hypoxia-induced miR-210 up-regulation seems to be able to directly enhance tumour angiogenesis by targeting EphrinA3 and ROD1.