适配体药物AS1411下调星形胶质细胞外泌体MiRNA-27a靶向INPP4B抑制脑胶质瘤增殖的机制研究

脑胶质瘤与星形胶质细胞（Astrocytes，AC）的交互作用能促进该肿瘤增殖，AC外泌体携带的miRNA可能参与其中，但相关机制尚不明确。申请人前期发现适配体药物AS1411不仅直接抑制脑胶质瘤增殖，还能减轻AC的促脑胶质瘤增殖的作用，并初步确认AC外泌体miRNA-27a及其靶基因INPP4B在其中发挥关键作用。据此提出科学假说：AS1411通过下调AC外泌体miRNA-27a靶向INPP4B抑制脑胶质瘤增殖。本项目拟确认miRNA-27a的靶基因是抑癌因子INPP4B，探讨AS1411能否下调AC外泌体miRNA-27a从而靶向上调脑胶质瘤中INPP4B的表达，继而抑制PI3K/AKT通路、抑制脑胶质瘤增殖，并在小鼠脑胶质瘤模型中进行验证，为阐明AS1411抗肿瘤机制及研发脑胶质瘤治疗药物提供新的思路。

The interaction between glioma and astrocytes (AC) can promote the proliferation of glioma. MiRNAs carried by AC exosomes may be involved in this process, but the mechanism remains unclear. Preliminary experiments showed that the aptamer AS1411 could directly inhibit the proliferation of glioma and reduce the astrocytes’ pro-glioma activity. Then we preliminarily screened and confirmed that AC exosome miRNA-27a and its target gene tumor suppressor inositol polyphosphate-4-phosphatase type II (INPP4B) played a crucial in this process. Thus, we propose that AS1411 inhibits the proliferation of glioma by reducing AC exosome miRNA-27a to target INPP4B. In this project, we intend to verify that the target gene of miRNA-27a is the INPP4B. Subsequently, we explore whether AS1411 can down-regulate AC exosome miRNA-27a and up-regulate the expression of INPP4B in glioma, thereby inhibiting PI3K/AKT pathway and inhibiting glioma proliferation. Finally, it is verified in the mouse glioma model. This study provides a new way to elucidate the anti-tumor mechanism of AS1411 and to develop new drugs for the treatment of glioma.