Circular RNAs (circRNAs) are a type of endogenous non-coding RNAs, which have been considered to mediate diverse tumorigenesis including angiogenesis. The present study aims to elucidate the potential role and molecular mechanism of circ-SHKBP1 in regulating the angiogenesis of U87 glioma-exposed endothelial cells (GECs). The expression of circ-SHKBP1, but not linear SHKBP1, was significantly upregulated in GECs compared with astrocyte-exposed endothelial cells (AECs). circ-SHKBP1 knockdown inhibited the viability, migration, and tube formation of GECs dramatically. The expressions of miR-379/miR-544a were downregulated in GECs, and circ-SHKBP1 functionally targeted miR-544a/miR-379 in an RNA-induced silencing complex (RISC) manner. Dual-luciferase reporter assay demonstrated that forkhead box P1/P2 (FOXP1/FOXP2) were targets of miR-544a/miR-379. The expressions of FOXP1/FOXP2 were upregulated in GECs, and silencing of FOXP1/FOXP2 inhibited the viability, migration, and tube formation of GECs. Meanwhile, FOXP1/FOXP2 promoted angiogenic factor with G patch and FHA domains 1 (AGGF1) expression at the transcriptional level. Furthermore, knockdown of AGGF1 suppressed the viability, migration, and tube formation of GECs via phosphatidylinositol 3-kinase (PI3K)/AKT and extracellular signal-regulated kinase (ERK)1/2 pathways. Taken together, the present study demonstrated that circ-SHKBP1 regulated the angiogenesis of GECs through miR-544a/FOXP1 and miR-379/FOXP2 pathways, and these findings might provide a potential target and effective strategy for combined therapy of gliomas.

环状RNA（circRNA）是一类内源性非编码RNA，被认为介导多种肿瘤发生，包括血管生成。本研究旨在阐明circ-SHKBP1在调节U87胶质瘤暴露的内皮细胞（GEC）血管生成中的潜在作用和分子机制。与暴露于星形胶质细胞的内皮细胞 (AEC) 相比，GEC 中 circ-SHKBP1 的表达显着上调，但线性 SHKBP1 的表达不显着上调。circ-SHKBP1 敲低显着抑制了 GEC 的活力、迁移和管形成。GEC 中 miR-379/miR-544a 的表达下调，并且 circ-SHKBP1 以 RNA 诱导的沉默复合物 (RISC) 方式功能性靶向 miR-544a/miR-379。双荧光素酶报告基因测定表明叉头盒 P1/P2 (FOXP1/FOXP2) 是 miR-544a/miR-379 的靶标。GEC 中 FOXP1/FOXP2 的表达上调，FOXP1/FOXP2 的沉默抑制了 GEC 的活力、迁移和管形成。同时，FOXP1/FOXP2在转录水平促进血管生成因子G patch和FHA结构域1（AGGF1 ）的表达。此外，AGGF1 的敲低通过磷脂酰肌醇 3 激酶 (PI3K)/AKT 和细胞外信号调节激酶 (ERK)1/2 途径抑制 GEC 的活力、迁移和管形成。综上所述，本研究表明，circ-SHKBP1通过miR-544a/FOXP1和miR-379/FOXP2通路调节GEC的血管生成，这些发现可能为胶质瘤的联合治疗提供潜在的靶点和有效策略。