Circular RNA-936靶向结合miR-379/544a基因簇调控胶质瘤血管新生的分子机制

前期发现环状RNA-936在胶质瘤微血管内皮细胞(GECs)中高表达，下调环状RNA-936的表达抑制GECs的增殖、迁移和管形成。通过系列前期工作推测，GECs中高表达的环状RNA-936可能通过与miR-379/544a靶向结合抑制靶基因的表达。一方面miR-379通过FoxP2、另一方面miR-544a通过FoxP1，间接调控血管新生相关因子AGGF1的表达共同影响胶质瘤血管新生。本项目先研究环状RNA-936和miR-379/544a的靶向结合作用，阐明环状RNA-936通过miR-379/544a影响胶质瘤血管新生的作用机制；然后研究miR-379/544a分别与FoxP2、FoxP1的靶向结合作用，明确miR-379/544a调控AGGF1的分子机制；最后明确环状RNA-936抑制剂、miR-379/544a单独以及联合应用抑制胶质瘤血管新生的效应，为胶质瘤治疗提供新途径。

Our previous study demonstrated Circular RNA-936 (hsa_circ_0000936) was higher expressed in glioma microvascular endothelial cells (GECs). However, miR-379 and miR-544a encoded by miR-379/544a cluster were downregulated in GECs. Both miR-379 and miR-544a were predicted to contain putative binding sites of Circular RNA-936 with the help of starBase v2.0. Downregulation of Circular RNA-936 inhibited proliferation, migration and tube formation of GECs. According to previous findings, we speculate overexpression of Circular RNA-936 in GECs might respectively target miR-379 and miR-544a to inhibit expression of their target genes. On the one hand, miR-379 indirectly regulates expression of angiogenic factor with G-patch and FHA domains 1 (AGGF1) and further affects angiogenesis of glioma by targeting transcription factor forkhead box P2 (FoxP2). On the other hand, miR-544a indirectly regulates expression of AGGF1 and further affects angiogenesis of glioma by targeting transcription factor forkhead box P1 (FoxP1). In the present study, we firstly investigate the targeting combination of Circular RNA-936 and miR-379/544a to elucidate action mechanism of Circular RNA-936 regulating angiogenesis of glioma by targeting miR-379/544a. Secondly, we study the targeting combination of miR-379/544a and FoxP2、FoxP1 respectively as well as their binding sites to clarify molecular mechanism of miR-379/544a regulating AGGF1. Finally, we elucidate effects of Circular RNA-936 inhibitor, miR-379/544a alone and their combination inhibiting angiogenesis of glioma in order to provide novel ideas for antiangiogenic therapy of glioma.