Abstract
Glioblastoma is a rare yet lethal type of tumor that poses a crucible for the medical profession, owing to its rapid proliferation and invasion resulting in poor prognosis. Circular RNAs (circRNAs), a subclass of regulatory RNAs, are implicated in the regulation of cancerous progression. This study aims to investigate the roles and underlying mechanism of circPIK3C2A in regulating proliferation and invasion of glioblastoma. qRT-PCR assays showed that the expression level of circPIK3C2A was aberrantly higher in glioblastoma cell lines, in comparison with that in normal glia cells. The ectopic expression of circPIK3C2A promoted the proliferation, invasion and clonal formation of glioblastoma cells, while circPIK3C2A loss-of-function exerted exactly the opposite biological effects on the cells. The construction of subcutaneous xenograft tumor model in nude mice indicated that circPIK3C2A loss-of-function effectively diminished tumor load in vivo and prolonged the survival time of tumor-bearing animals. Luciferase reporter assay confirmed the interaction among circPIK3C2A/miR-877-5p and FOXM1. CircPIK3C2A function as competitive endogenous RNA via sponging miR-877-5p through certain binding sites, thereby modulating the expression of FOXM1. Our results collectively indicate that circPIK3C2A functions as ceRNA by mediating miR-877-5p/FOXM1 axis, providing a novel perspective of applying CircPIK3C2A in the clinical intervention of glioblastoma in the future.
Highlights
Glioblastoma multiforme (GBM) is the most common and aggressive type of brain cancer with grade IV histological malignancy, according to the classification of WHO [1]
CircPIK3C2A contains one exon that creates a transcript of 1310 nucleotides by back-splicing (Figure 1A). circPIK3C2A cDNA coincident with approximately 100 bp upstream and downstream from the junction site was amplified in GBM cells using divergent primers and was analyzed by using Sanger sequencing
The results showed that miR-877-5p decreased the luciferase activity of the WT reporter for FOXM1, but not that of the MUT-type reporter, which confirmed miR877-5p as a sponge target of FOXM1 in U87-MG and U251-MG cells (Figures 5D–F). qPCR results indicated that miR-877-5p reduced the expression levels of FOXM1, while circPIK3C2A overexpression reversed the effects of miR-877-5p (Figures 5G, H)
Summary
Glioblastoma multiforme (GBM) is the most common and aggressive type of brain cancer with grade IV histological malignancy, according to the classification of WHO [1]. Significant advances have been made in the diagnosis and treatment of GBM, the clinical outcomes of patients. GBM patients may benefit from personalized therapies that targets certain molecular biomarkers, many potential treatments are counterbalanced by strong side effects in clinical trials or prove to be of little efficacy [3]. Under such circumstances, it is necessary to perform intensified exploration into the molecular mechanism and the intricate gene regulation network that underlies the onset and progression of GBM, so as to determine novel therapeutic candidates and devise more promising treatment strategies for GBM
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