miR-106a/MGLL调控TAMs活化促进黑色素瘤恶性进展的效应及机制研究

代谢重编程介导肿瘤相关巨噬细胞（TAMs）发生活化，调控肿瘤恶性进展，而黑色素瘤TAMs发生代谢重编程及M2活化的机制和效应尚不明了。在上一项目深入研究TAMs脂代谢重编程时，我们意外发现另一重要的脂肪分解因子MGLL，可能在TAMs活化及黑色素瘤恶性进展中起关键作用。本研究拟在黑色素瘤-巨噬细胞共培养体系、巨噬细胞转基因小鼠及临床样本中，考察黑色素瘤对TAMs HIF-1α/miR-106a的调节作用；解析miR-106a调控MGLL的分子机制；揭示巨噬细胞miR-106a/MGLL调控2-AG/CB2信号，诱导M2活化的机制及效应；统计关键分子与黑色素瘤进展的相关性。本研究以TAMs脂质代谢异常为切入点，率先解析miR-106a/MGLL通路介导的CB2大麻素信号在TAMs M2活化及黑色素瘤恶性进展中的作用及机制，研究结果对于从肿瘤微环境角度寻找黑色素瘤的防治策略具有重要指导意义。

Metabolic reprogramming-mediated activation of tumor associated macrophages (TAMs) is causally linked to the tumor development, with the metabolic reprogramming and M2 polarization in the TAMs in melanoma being not fully elucidated. When exploring the lipid reprogramming in TAMs in our previous project, we found that another important adipolytic factor MGLL might regulate TAM activation and melanoma development. By using the co-culture system of melanoma and macrophages, macrophage-specific transgenic mice as well as clinical samples, we are to decipher the regulatory effects of melanoma on HIF-1α/miR-106a in TAMs, to elucidate the regulatory mechanisms of miR-106a on MGLL, to uncover the roles of miR-106a/MGLL pathway on 2-AG/CB2 signaling-mediated M2 activation and tumor progression, and to analyze the correlations between the key molecules and the malignant progression of melanoma in clinics. This project initiated with the abnormal lipid metabolism in TAMs and would investigate the novel roles of miR-106a/MGLL pathway-mediated CB2 signaling in M2 polarization and melanoma progression. Our findings would shed light on the management of melanoma in a novel angle of tumor microenvironment.