TIPE2通过调控有氧糖酵解调节肿瘤相关巨噬细胞促肿瘤作用的研究

Tumor-associated macrophages (TAMs) have an M2 phenotype and can activate the AKT-mTOR pathway in response to the stimulation of microenvironment. After the AKT-mTOR activation, TAMs upregulate the expression of key glycolytic enzymes in a way of transcriptional activation or histone acetylation, initiate the process of aerobic glycolysis, rapidly synthesize and secrete negative regulators, and promote the malignant progression of tumors. Exploring the mechanism of this process is important for reversing the tumor-promoting effects of TAMs. The negative immune regulatory molecule TIPE2 is highly expressed in myeloid immune cells and can promote macrophage polarization toward the M2 phenotype by activating the AKT pathway. The applicant's previous study found that TIPE2 can participate in the synthesis and secretion of negative regulators and tumor promotion by regulating the aerobic glycolysis process of TAMs, and this effect is mediated through the AKT-mTOR pathway. It is hypothesized that TIPE2 can regulate the tumor-promoting effect of TAMs by regulating their aerobic glycolysis, which is achieved by transcriptional activation or histone acetylation of the key glycolytic enzymes after activation of the AKT-mTOR pathway. This project will elucidate the molecular mechanism of TIPE2-regulated aerobic glycolysis in TAMs, in order to reverse its tumor-promoting effects and to provide new therapeutic strategies and targets for cancer therapy.

肿瘤相关巨噬细胞TAMs具有M2表型，能在微环境刺激下活化AKT-mTOR通路，以转录激活或组蛋白乙酰化修饰的方式促进糖酵解关键酶的表达，启动有氧糖酵解进程，快速合成分泌负性调节因子，促进肿瘤的恶性进展。探明这一过程的发生机制，对于逆转TAMs的促肿瘤作用具有重要意义。负性免疫调控分子TIPE2在髓系免疫细胞中高表达，并可通过激活AKT通路促进巨噬细胞向M2型极化。申请人前期研究发现，TIPE2能通过调控TAMs的有氧糖酵解进程，参与其负性调节因子的合成分泌及促肿瘤作用，且这一作用通过AKT-mTOR通路介导。由此提出研究假设：TIPE2能通过调控TAMs的有氧糖酵解进程，调节其促肿瘤作用，这一作用是通过AKT-mTOR通路活化后，对糖酵解关键酶的转录激活或组蛋白乙酰化修饰实现的。本项目将阐明TIPE2调控TAMs有氧糖酵解的分子机制，以逆转其促肿瘤作用，为肿瘤治疗提供新的治疗策略与靶点。

肿瘤相关巨噬细胞TAMs具有M2表型，能在微环境刺激下活化AKT-mTOR通路，以转录激活或组蛋白乙酰化修饰的方式促进糖酵解关键酶的表达，启动有氧糖酵解进程，快速合成分泌负性调节因子，促进肿瘤的恶性进展。探明这一过程的发生机制，对于逆转TAMs的促肿瘤作用具有重要意义。负性免疫调控分子TIPE2在髓系免疫细胞中高表达，并可通过激活AKT通路促进巨噬细胞向M2型极化。本项目在前期研究的基础上拟定了研究目标，首先希望在动物模型中，验证TIPE2通过调控TAMs对肿瘤进展的促进作用；明确这一宏观作用后，在体外实验中阐明TIPE2通过调控有氧糖酵解对TAMs的调节作用；并且在分子水平，解析这一调控的分子机制，是通过具体哪条信号通路或分子作用来实现的。围绕上述研究目标，本项目首先在WT和TIPE2-/-小鼠的皮下成瘤模型中，通过巨噬细胞特异性抗体CSFR1的应用，证实了TIPE2能够通过调控TAMs促进肿瘤的恶性进展；接下来通过在体外建立巨噬细胞与小鼠肿瘤细胞的共培养体系，阐明了TIPE2能够通过有氧糖酵解进程对TAMs的迁移、分泌等功能进行调节；最后在分子水平的实验中，解析了TIPE2调控TAMs有氧糖酵解进程中，AKT通路所发挥的重要作用，并且发现了TIPE2-/- TAMs中葡萄糖转运体Glut1所发生的质膜定位改变。发现了TAMs调控肿瘤进展的新机制，并为从该群细胞入手抑制肿瘤恶性进展提供了新线索和思路。