外泌体-miR-23b诱导恶性胶质瘤有氧糖酵解的机制研究

Increasing evidences have revealed that aerobic glycolysis exists in glioma and plays a critical role in tumorigenesis. Moreover, targeting aerobic glycolysis presents a promising strategy for cancer therapy. In the previous study, we found exo-miR-23b characteristically expressed and secreted by hypoxic cells. It is important to note that the abnormally activated Wnt/β-catenin signaling pathway enhanced the expression of miR-23b. Exo-miR-23b could transfer to normaxic cells and promote aerobic glycolysis metabolism process. The potential mechanism may be miR-23b directly targets the 3’ UTR region of TUSC2 and PGC-1α. Based on the above results, we aimed to explore the mechanism of exo-miR-23b induced by hypoxic glioma cells modulates the aerobic glycolysis. To solve the following problems: firstly, investigate the activity of Wnt/β-catenin signaling pathway and expression of exo-miR-23b in hypoxic glioma cells. Furthermore, Wnt/β-catenin pathway could regulate miR-23b expression by binding to the promoter region. In addition, exo-miR-23b secreted from hypoxic cells triggers the aerobic glycolysis switch of normoxic glioma cells in vitro and vivo. Finally, validate the mechanism of exo-miR-23b in normoxic glioma cells could directly target TUSC2 and PGC-1α. Taken together, this subject research will define novel insights into the tumor energy metabolism and provide an importantly experimental groundwork for the development of a promising target for clinical therapy of aerobic glycolysis.

干扰有氧糖酵解的发生，切断其能量供应是胶质瘤治疗的新策略。前期研究发现，乏氧胶质瘤细胞通过Wnt/β-catenin通路诱导exo-miR-23b的表达，促使常氧细胞发生有氧糖酵解。其可能机制是：靶向下调TUSC2、PGC-1α的表达，使靶细胞线粒体功能受损的同时激活与有氧糖酵解相关信号通路。本课题拟解决以下问题：明确胶质瘤乏氧状态、Wnt/β-catenin通路活性与exo-miR-23b的表达及相关性；验证β-catenin/TCF4转录调控miR-23b；体内外实验证实exo-miR-23b调控胶质瘤细胞糖代谢及成瘤能力；进一步探索exo-miR-23b靶向调控TUSC2、PGC-1α诱导胶质瘤细胞有氧糖酵解的机制。研究miRNA对胶质瘤细胞能量代谢的调控，将为破解胶质瘤基于能量代谢异常而表现出的恶性生物学行为提供重要线索，也将为其治疗提供新的思路。

干肿瘤细胞来源的外泌体-miRNAs由于其自身的特性和功能特点，在肿瘤细胞与肿瘤微环境的交流中充当信息载体，是目前肿瘤研究领域的热点问题。miRNA 能够通过对肿瘤细胞葡萄糖摄取、糖酵解途径、三羧酸循环以及脂代谢和氨基酸代谢与三羧酸循环的联系等途径中的关键环节进行调控，结果使肿瘤细胞对葡萄糖的摄取和糖酵解处于增高状态。乏氧胶质瘤细胞通过Wnt/β-catenin通路诱导exo-miR-23b的表达，促使常氧细胞发生有氧糖酵解。本项目研究恶性胶质瘤乏氧细胞特异性表达Exo-miR-23b的机制，揭示其与恶性胶质瘤有氧糖酵解之间的关系并鉴定其调控靶基因，其分子作用机制是：靶向下调TUSC2、PGC-1α的表达，使靶细胞线粒体功能受损的同时激活与有氧糖酵解相关信号通路。本课题明确了胶质瘤细胞中乏氧与Wnt/β-catenin信号通路异常激活之间的作用，以及β-catenin/TCF4对miR-23b的转录调控作用；初步探索Exo-miR-23b对常氧胶质瘤细胞生物学行为以及有氧糖酵解的影响，靶向癌基因和抑癌基因以改变癌细胞代谢方式、直接干预有氧糖酵解以阻断肿瘤细胞能量供应；揭示Exo-miR-23b与肿瘤微环境之间的异常调节和有氧糖酵解的分子机制，证明肿瘤细胞能量代谢的生化特征改变涉及多基因、多分子和多水平的调控，为靶向有氧糖酵解过程而选择性杀灭肿瘤细胞的治疗策略提供理论基础，达到针对肿瘤细胞的可塑性和内环境治疗肿瘤的目的。