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

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.

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。

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、结肠癌等实体肿瘤的TAMs发生代谢重编程及M2活化的机制和效应尚不明了。本项目旨在揭示脂代谢重编程对肿瘤微环境的影响及具体机制，有望从代谢干预的角度为肿瘤防治提供潜在靶点。在本项目及相关课题的资助下，我们发现：（1）黑色素瘤、结直肠癌、乳腺癌等肿瘤来源的巨噬细胞，其甘油一酯水解酶MGLL表达降低。巨噬细胞MGLL转基因可抑制，而CB2转基因可促进黑色素瘤和结肠癌的小鼠移植瘤。其机制为：MGLL通过调控CB2/TLR4相互作用，进而调控巨噬细胞活化和CD8+ T细胞活化。（2）单细胞测序表明肿瘤相关巨噬细胞ABHD5表达呈现异质性。ABHD5低表达的巨噬细胞与结直肠癌迁移活性正相关。ABHD5 低表达后，通过激活p65，进而促进基质金属蛋白酶家族表达上调，从而促进黑色素瘤和结肠癌的腹腔种植和肺部转移。（3）AGPAT4在结肠癌组织高表达，并与结肠癌不良预后相关。AGPAT4敲低不影响结肠癌细胞体外的生长、迁移、周期、凋亡等活性，却可显著抑制结肠癌细胞在小鼠体内的生长。AGPAT4调节癌细胞LPA的生成和释放，通过LPA1/3受体活化巨噬细胞为M1，进而活化T细胞抗瘤免疫。本项目锁定肿瘤相关巨噬细胞，从肿瘤微环境脂代谢的角度，为黑色素瘤、结肠癌等肿瘤的防治提供了多个潜在的干预靶点，具有重要意义。此外，在项目执行期间，突发新冠疫情，我们还额外进行了新冠疾病临床研究。我们筛选和验证了多个可用于新冠疾病分型和转归预测的临床指标，首创基于外周血淋巴细胞计数的新冠疾病分型和转归预测模型，及时报道了病毒排出时间长达49天的轻症新冠病例，为新冠疾病的临床管理和预防决策提供了重要依据。