靶向AGR2治疗胶质母细胞瘤干细胞的应用及机制研究

胶质母细胞瘤干细胞(Glioblastoma stem cells, GSCs)呈低分化乃至静止状态，放化疗均不敏感，从而使胶质母细胞瘤(GBM)易复发。前期发现前梯度蛋白2（Anterior gradient protein 2，AGR2）在GSCs中特异性高表达，但在正常神经干细胞内很少表达，设计干扰载体对AGR2进行阻断后，肿瘤细胞的迁移和侵袭能力显著下降，小鼠生存时间显著延长。结果表明靶向抑制AGR2具备治疗脑胶质瘤潜力。预实验提示AGR2和HIF-1α的表达呈高度相关，我们推测：AGR2可能通过HIF-1α维持GSCs的干性，促进GBM的复发。本课题组拟①构建载体、分别干扰或过表达GSCs内的AGR2与HIF-1α；②验证AGR2，HIF-1α通路内蛋白的作用及细胞内定位关系；③动物模型评估干扰AGR2靶向GSCs安全性和有效性，为GBM的靶向治疗提供新的策略和科学依据。

Glioblastoma stem cells (GSCs) are poorly differentiated and even quiescent, and are insensitive to chemoradiotherapy, which leads to glioblastoma (GBM) prone to recurrence.Studies have shown that targeting GSCs is a feasible therapeutic option, but safe and reliable targets are urgently needed. Our group previously isolated GSCs from glioma mice and found that AGR2 was specifically and highly expressed in GSCs by transcriptome sequencing and immunofluorescence, while it was rarely expressed within normal neural stem cells..After the design of interference vectors to block AGR2, the migration and invasion of tumor cells were significantly decreased, and the survival time of mice was significantly prolonged.The results indicate that targeted inhibition of AGR2 has potential for the treatment of gliomas.Preliminary experiments suggested that the expression of AGR2 and HIF-1α was highly correlated, and we speculated that: AGR2 may maintain the stemness of GSCs and promote the recurrence of GBM through HIF-1α. Our group intends to ① construct vectors and interfere or overexpress AGR2 and HIF-1α in GSCs, respectively; ② molecular experiments to verify the role of AGR2, proteins in the HIF-1α pathway and intracellular localization relationship; ③ animal models to evaluate the safety and efficacy of interfering AGR2 targeting GSCs and provide a new strategy and scientific basis for targeted therapy of GBM.