FUS/circ_002136/miR-138-5p/SOX13 feedback loop regulates angiogenesis in Glioma

Abstract

BackgroundAngiogenesis plays a critical role in the progression of glioma. Previous studies have indicated that RNA-binding proteins (RBPs) interact with RNAs and participate in the regulation of the malignant behaviors of tumors. As a type of endogenous non-coding RNAs, circular RNAs (circRNAs) are abnormally expressed in various cancers and are involved in diverse tumorigeneses including angiogenesis.MethodsThe expression levels of FUS, circ_002136, miR-138-5p, SOX13, and SPON2 were determined using quantitative real-time PCR (qRT-PCR) and western blot. Transient cell transfection was performed using the Lipofectamine 3000 reagent. The RNA-binding protein immunoprecipitation (RNA-IP) and the RNA pull-down assays were used to detect the interaction between FUS and circ_002136. The dual-luciferase reporter assay system was performed to detect the binding sites of circ_002136 and miR-138-5p, miR-138-5p and SOX13. The chromatin immunoprecipitation (ChIP) assays were used to examine the interactions between transcription factor SOX13 and its target proteins .ResultsWe demonstrated that down-regulation of FUS or circ_002136 dramatically inhibited the viability, migration and tube formation of U87 glioma-exposed endothelial cells (GECs). MiR-138-5p was down-regulated in GECs and circ_002136 functionally targeted miR-138-5p in an RNA-induced silencing complex (RISC). Inhibition of circ_002136, combined with the restoration of miR-138-5p, robustly reduced the angiogenesis of GECs. As a target gene of miR-138-5p, SOX13 was overexpressed in GECs and was proved to be involved in circ_002136 and miR-138-5p-mediated angiogenesis in gliomas. In addition, we found that SOX13 was directly associated with and activated the SPON2 promoter, thereby up-regulating the expression of SPON2 at the transcriptional level. Knockdown of SPON2 suppressed the angiogenesis in GECs. More important, SOX13 activated the FUS promoter and increased its expression, forming a feedback loop.ConclusionOur data suggests that the feedback loop of FUS/circ_002136/miR-138-5p/SOX13 played a crucial role in the regulation of angiogenesis in glioma. This also provides a potential target and an alternative strategy for combined glioma therapy.Electronic supplementary materialThe online version of this article (10.1186/s13046-019-1065-7) contains supplementary material, which is available to authorized users.

Spondin 2 promotes the proliferation, migration and invasion of gastric cancer cells

“…33 The non-coding RNAs that are abnormally expressed can also first increase the expression level of its target gene SOX13, and then activating the promoter region of SPON2 by SOX13 to increase the expression level of SPON2 in glioma tissues. 34 There may be similar thyroid hormone and non-coding RNA expression abnormalities in GC tissues, which requires further study in the future. [35][36][37] Here we show that the serum levels of SPON2 were significantly Our research shows that down-regulation of SPON2 expression arrested GC cells in G1 and decreased the number of cells in S phase.…”

circCPA4 acts as a prognostic factor and regulates the proliferation and metastasis of glioma

“…A study revealed that more than 476 circRNAs were differentially expressed in glioma . And circ_002136 was found to inhibit the viability, migration and tube formation of glioma . Here, we performed high‐throughput circRNA microarray assays of glioma tissues and matched normal brain tissue samples to investigate the involvement of circRNAs in glioma.…”

“…16 And circ_002136 was found to inhibit the viability, migration and tube formation of glioma. 17 Here, we performed high-throughput circRNA microarray assays of glioma tissues and matched normal brain tissue samples to investigate the involvement of circRNAs in glioma. The result showed that circCPA4 (hsa_ circ_0082374) up-regulated the most in glioma and high levels of circCPA4 were positively associated with poorer survival of glioma ( Figure 1).…”

TRA2A-induced upregulation of LINC00662 regulates blood-brain barrier permeability by affecting ELK4 mRNA stability in Alzheimer’s microenvironment

“…RBP QKI is highly expressed in ECs and promotes the mRNA of β-catenin and VE-cadherin translation by binding with them, which contributes to maintenance of endothelial barrier function [39] . RBPs MOV10 and FUS regulate vascular endothelial function by binding to Circular RNAs (circRNAs) [40,41] .…”