Circular RNA hsa_circ_0076248 promotes oncogenesis of glioma by sponging miR‐181a to modulate SIRT1 expression

Abstract

Glioma is one of the most common primary malignancies of the central nervous system, which has aggressive clinical behavior and a poorer prognosis. MicroRNAs (miRs) are a class of small noncoding RNAs that function as mediators of gene expression, which can be sponged by circRNA provided with a closed circular structure. Dysregulations of circular RNAs (circRNAs) and miRs have been implicated in the development and progression of glioma. In the current study, we investigated the role of circular RNA hsa_circ_0076248 in mediating the oncogenesis of glioma by sponging miR‐181a to modulate silent information regulator 1 (SIRT1) expression in vitro and in vivo. The quantitative real‐time polymerase chain reaction results showed that the expression of miR‐181a was significantly decreased in glioma tissues and cell lines compared with normal brain tissues and normal gliocyte, respectively, and the expression of hsa_circ_0076248 and SIRT1 demonstrated the opposite. Bioinformatics analysis identified hsa_circ_0076248 could sponge miR‐181a, and miR‐181a could target the mRNA of SIRT1. Our results verified that downregulating hsa_circ_0076248 or upregulating miR‐181a could depress the proliferation and invasion of glioma in vitro and in vivo. The experiment also showed that downregulating hsa_circ_0076248 or upregulating miR‐181a could remarkably promote the temozolomide chemotherapy sensitivity. Furthermore, Western blot analysis testified that downregulating hsa_circ_0076248 or upregulating miR‐181a could promote the expression of p53 and SIRT1. In summary, our study sheds light on the regulatory mechanism of hsa_circ_0076248 in glioma growth and invasion via sponging miR‐181a, which downregulates the SIRT1 expression and also suggests that hsa_circ_0076248, miR‐181a, and SIRT1 may serve as potential therapeutic targets for glioma.

Functions and clinical significance of circular RNAs in glioma

“…Also, circRNA HIPK3 exhibited sponging multiple miRNAs, including tumor suppressor miR-124, miR-7, miR-4288, miR-654 [46,[49][50][51]. Previous studies indicated that circ_0034642 and circ_0076248 promoted glioma proliferation and invasion in the miR-1205/BATF3 axis and miR-181a/SIRT1 axis, respectively [52,53]. It seemed that these findings support the notion that the roles of circRNAs as miRNA sponge may be a general phenomenon.…”

“…Also, exosomal miR-1238 may confer chemoresistance in the tumor microenvironment, indicating that circulating miR-1238 acted as a promising therapeutic target for TMZ resistance in GBM [125]. Lei et al demonstrated that down-regulated hsa_circ_ 0076248 could remarkably promote the TMZ chemotherapy sensitivity via sponge miR-181a, which could suppress the expression of silent information regulator 1 (SIRT1) [52]. All these researches tend to make circRNAs become promising diagnostic/prognostic biomarkers and novel therapeutic targets.…”

“…The relationship between miRNAs and tumor immunity is explicit, while circRNA is closely associated with antitumor immunity based on the theory of binding to miRNAs, proteins, Besides, circRNAs in tumor exosomes serve as tumor antigens to activate antitumor immunity, indicating a potential target for immunotherapy. For instance, miR-138 could target CTLA-4 and PD-1 to escape from immune checkpoint therapy in glioma [128], hence,circ_002136 may also has a potential immunotherapy target through sponging miR138 [107], IL-6R by circHIPK3-miR124 axis may affect gliomas immune response [80], circ_0076248 could participate in immune response by regulating expression of p53 and SIRT1 mediated by miR-181a [52], Furthermore, miR-34a overexpression remarkably weakened PD-L1-induced chemoresistance, supporting that miR-34a is a negative regulator of PD-L1 signaling in glioma [129]. Based on the fact miR-34a could be sponged by cir-cNFIX, suggesting circNFIX may play essential roles in immunotherapy of gliomas [77].…”

Elevation of circ‐PITX1 upregulates interleukin 17 receptor D expression via sponging miR‐518a‐5p and facilitates cell progression in glioma

“…[14][15][16] The aberrant expression of circRNA has been found in a wide variety of tumors, including GM. [10][11][12][13] For example, Lei et al 17 revealed that hsa_circ_0076248 could promote GM tumorigenesis through sponging miR-181a and regulate SIRT1 expression. Nevertheless, our knowledge of the roles of circRNAs might play in GM is still very limited.…”

CircNFIX promotes progression of glioma through regulating miR-378e/RPN2 axis

“…They are distributed in neuronal tissues and exhibit key functions in brain diseases, including glioma [4,5]. For instance, Lei et al reported that circRNA hsa_circ_0076248 promotes proliferation and invasion of glioma by regulating miR-181 and silent information regulator 1 (SIRT1) [6]. Shi et al showed that hsa_circ_0014359 contributes to glioma progression by targeting miR-153/phosphatidylinositol 3 kinase (PI3K) signaling [7].…”