In the present study we used a microRNA microarray assay to study the differential expression pattern of microRNA in pediatric gliomas and the matched adjacent noncancerous tissues. Among the microRNAs detected in the microarray, we identified 40 microRNAs showing significantly higher or lower expression levels in tumors compared to the matched normal tissues. Results of GO analysis and KEGG pathway analysis suggested that target genes were closely associated with nervous system-related and tumor-related biological processes and signaling pathways.
Some of the microRNAs that showed differential expression between brain tumors and normal tissues in our study had previously been studied or found to be associated with gliomas, including pediatric gliomas. MiR-21, which was discovered to be upregulated by us, was also found and validated to be with increased expression in pediatric pilocytic astrocytoma (PA), a World Health Organization grade I pediatric glioma, in the study of Ho CY et al. . Overexpression of miR-222 in gliomas was also observed by the research of Li Q et al. . They proved that miR-222 could regulate Wnt/β-catenin signaling pathway and promote glioma genesis by using RNA interference and western blot technology. Furthermore, downregulation of miR-204, which was found to be associated with gliomas in our study, was also proved to contribute to glioma migration by targeting the migration-promoting receptor EphB2 . In the present study miR-218 was discovered to be with decreased expression in pediatric gliomas, indicating the reverse relationship between miR-218 expression and development of gliomas. This was consistent with the findings of Tu Y et al. . They found that upregulation of miR-218 reduced the migration, invasion and proliferation of glioma cells dramatically by regulating a wide range of genes and pathways. A new target gene of miR-218, which was noticed to be down-regulated in glioma in our study, has recently been found in the study of Shi ZM et al. . They identified p70S6K1 as a novel direct target of miR-128 and overexpression of p70S6K1 can partly rescue the inhibitory effect of miR-128 in the glioma cells. This result further confirms our findings.
As expected, some of the microRNAs that showed differential expression in gliomas in our data were novel. There is little evidence about the relationship between miR-1321, miR-513b, miR-769-3p and cancer genesis. In addition, the upregulated microRNAs including miR-424*, miR-760, miR-513b, miR-361-5p, miR-1259, miR-363, miR-199a, miR-1827, miR-423-5p, miR-1308, miR-1274, miR-1224, miR-513b and the downregulated microRNAs including miR-885, miR-769, miR-1296, miR-192, miR-331-3p, miR-484, miR-99b were found to be related with gliomas for the first time. This may provide new clues for gliomas research.
Aberrant expression of microRNAs may contribute to the induction of pediatric gliomas by regulating genes involved in nervous system-related and tumor-related biological processes and signaling pathways. According to the result of GO analysis, the target genes were involved in negative regulation of neuron apoptosis, axonogenesis, regulation of synaptic transmission, neurotransmitter secretion and synaptic vesicle transport et al.. These biological processes are crucial for maintaining normal functioning of the nervous system. Alteration of the processes induced by aberrant expression of certain microRNAs may favor glioma-genesis. As for biological pathways, several cancer-related pathways, including glioma, endometrial cancer, the TGF-beta signaling pathway, the MAPK signaling pathway, the wnt signaling pathway and the notch signaling pathway et al. were among the enriched pathways of the target genes. TGF-beta signaling has long been considered to contribute to glioma pathogenesis by direct support of tumor growth, self-renewal of glioma initiating stem cells and the inhibiting of anti-tumor immunity . Wnt signaling and MAPK signaling also play significant roles in almost all kinds of tumors, including glioma . In recent studies, notch signaling has been proved to be dysregulated in brain tumors and to contribute to the malignant potential of these tumors . Peng Xu et al. found out the different roles of Notch1 and Notch2. They proved that both upregulating of Notch1 and knocking down Notch2 had the effect of suppressing glioma cell growth and invasion as well as inducing apoptosis .
In conclusion, we investigated the changed expression patterns of microRNAs in pediatric gliomas and identified the possible role of microRNA and corresponding target genes in brain tumor pathology. However, due to the limitation of the microarray assay, only 866 known human microRNAs were detected. The role of more microRNAs in brain tumors needs to be investigated using more advanced techniques, such as second-generation sequencing and higher capacity microarrays. The present study does at least provide new insights into pediatric brain tumor biology and may assist in finding new diagnostic and therapeutic tools for these tumors.