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

Journal of Experimental & Clinical Cancer Research

Yixue Xue¹  Jun Ma¹  Zhenwei He¹  Lianqi Shao¹  Shuyuan Shen¹  Xuelei Ruan¹  Libo Liu¹  Jian Zheng²  Yunhui Liu²  Chunqing Yang²  Di Wang²  Xiaobai Liu² 

[1] Department of Neurobiology, School of Life Sciences, China Medical University;Department of Neurosurgery, Shengjing Hospital of China Medical University;

关键词: Angiogenesis;    FUS;    circ_002136;    miR-138-5p;    SOX13;    SPON2;   

DOI  :  10.1186/s13046-019-1065-7

来源: DOAJ

【 摘 要 】

Abstract Background Angiogenesis 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. Methods The 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 . Results We 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. Conclusion Our 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.

【 授权许可】

Unknown