Abstract
Circular RNAs (circRNAs) are a newly identifed non-coding RNA in many cellular processes and tumours. This study aimed to investigate the role of hsa_circ_0037251, one circRNA generated from several exons of the gene termed METRN, in glioma progression. Through in vitro experiments, we discovered that high expression of hsa_circ_0037251 was related to low expression of the microRNA miR-1229-3p and high expression of mTOR. The over-expressed hsa_circ_0037251 promoted cell proliferation, invasion and migration in glioma, while knockdown of hsa_circ_00037251 promoted cell apoptosis and induced G1 phase arrest. Then, hsa_circ_0037251 was observed to directly sponge miR-1229-3p, and mTOR was identified as a direct target of miR-1229-3p. In addition, knockdown of hsa_circ_0037251 up-regulated the expression of miR-1229-3p and inhibited the expression of mTOR. And overexpression of miR-1229-3p or low-expressed mTOR inhibited the glioma cell progression. Furthermore, transfection with mTOR overexpression vectors can restore the abilities of glioma cell progression even if hsa_circ_00037251 was knocked down using siRNAs. In vivo experiments revealed that hsa_circ_00037251 promoted the growth of xenografted tumours and shortened the survival period. These results indicated that hsa_circ_0037251 may act as a tumour promoter by a hsa_circ_0037251/miR-1229-3p/mTOR axis, and these potential biomarkers may be therapeutic targets for glioma.
Highlights
Www.nature.com/scientificreports studies have revealed that some circRNAs promote glioma carcinogenesis by decreasing the expression of miRNAs11,12
The exact mechanisms of the circRNA-miRNA network on target genes involved in cell proliferation, apoptosis, cell cycle regulation, invasion and migration remain unknown in glioma
Mammalian target of rapamycin protein is a highly conserved serine/threonine kinase that belongs to the PI3K-related kinase family19. mammalian target of rapamycin (mTOR) pathways were shown to be up-regulated in cell proliferation in brain tumours[20]
Summary
Www.nature.com/scientificreports studies have revealed that some circRNAs promote glioma carcinogenesis by decreasing the expression of miRNAs11,12. The exact mechanisms of the circRNA-miRNA network on target genes involved in cell proliferation, apoptosis, cell cycle regulation, invasion and migration remain unknown in glioma. Hsa_circ_0037251 is a circRNA generated from several exons of the gene encoding the meteorin protein (METRN), which was reported to play roles in both proliferation[17] and differentiation[18] of glioblasts. We generated deep RNA sequencing data from glioma samples and their paired adjacent normal tissues and identified miRNA and gene candidates, and we found that hsa_circ_0037251 was over-expressed in glioma tissues. The relationship between hsa_circ_0037251 and miR-1229-3p in glioma progression requires further investigation. We hypothesized that hsa_circ_0037251 might be involved in glioma progression by influencing the expression of mTOR in a miRNA-mediated manner.
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