Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
Department of Neurosurgery, The First Hospital of China Medical University, NO. 155 North Nanjing Street, Shenyang, 110001, China.
Oncogene. 2022 Jun;41(26):3461-3473. doi: 10.1038/s41388-022-02360-4. Epub 2022 May 30.
Glioblastoma multiforme (GBM) is the most lethal primary tumor with active neovascularization in the central nervous system. Studying the novel molecular mechanisms of GBM angiogenesis is very important. The glioblastoma-associated microglia (GAM) M2 polarization was constructed, and microglia-derived exosomes (MDEs) were isolated to co-culture with human brain microvessel endothelial cells (hBMECs). CircRNA sequence and molecular biological experiments were used to detect the expression levels and regulation functions among circKIF18A, FOXC2, ITGB3, CXCR4, DLL4 and the PI3K/AKT signaling. The functional effects of silencing or overexpression of these molecules were evaluated in hBMECs viability, invasion, and tube formation in vitro and tumorigenicity in vivo. M2 microglia polarization is positively correlated with microvessels' density in GBM patients. M2 GAM can promote the angiogenesis of GBM via transporting exosomal circKIF18A into hBMECs. Mechanistically, circKIF18A can bind to, maintain the stability and nuclear translocation of FOXC2 in hBMECs. Furtherly, as a transcription factor, FOXC2 can directly bind to the promoter of ITGB3, CXCR4, and DLL4 and upregulate their expressions. Besides, FOXC2 can also activate the PI3K/AKT signaling and promote the angiogenesis of GBM. Our study identified a novel molecular mechanism for M2 GAM-derived exosomal circKIF18A participating in GBM angiogenesis via targeting FOXC2. This may provide a novel treatment target to improve the outcomes for anti-angiogenic therapies in GBM.
多形性胶质母细胞瘤（GBM）是中枢神经系统中具有活跃新生血管形成的最致命的原发性肿瘤。研究 GBM 血管生成的新分子机制非常重要。构建了与胶质母细胞瘤相关的小胶质细胞（GAM）M2 极化，并分离小胶质细胞衍生的外泌体（MDE）与人类脑微血管内皮细胞（hBMEC）共培养。利用环状 RNA 序列和分子生物学实验检测 circKIF18A、FOXC2、ITGB3、CXCR4、DLL4 与 PI3K/AKT 信号之间的表达水平和调节功能。评估这些分子沉默或过表达对 hBMEC 体外活力、侵袭和管形成以及体内致瘤性的功能影响。M2 小胶质细胞极化与 GBM 患者的微血管密度呈正相关。M2 GAM 可以通过将外泌体 circKIF18A 转运到 hBMEC 中来促进 GBM 的血管生成。机制上，circKIF18A 可以与 hBMEC 中的 FOXC2 结合，维持其稳定性并促进其核转位。此外，作为转录因子，FOXC2 可以直接结合 ITGB3、CXCR4 和 DLL4 的启动子并上调其表达。此外，FOXC2 还可以激活 PI3K/AKT 信号通路并促进 GBM 的血管生成。我们的研究确定了一种新的分子机制，即 M2 GAM 衍生的外泌体 circKIF18A 通过靶向 FOXC2 参与 GBM 血管生成。这可能为改善 GBM 抗血管生成治疗的结果提供新的治疗靶点。
