微颗粒中microRNA-375经调控巨噬细胞的代谢与极化促进恶性胸腔积液的机制研究

Malignant pleural effusion (MPE), the severe feature of primary or metastatic pleural tumors, is difficult to control. Microparticles (MPs), known as "intercellular messenger", and macrophages are widely involved in the development of tumors. In the previous clinical study, we found that the level of miR-375 in MPs of MPE was significantly higher than that of benign pleural effusion, and bioinformatics analysis showed that the target genes of miR-375 are involved in metabolic pathways. We also found lung cancer cells-derived MPs prompt macrophages to M2 polarization. On this basis, the project intends to do following mechanism studies on how miR-375 inside microparticles regulate the metabolism and polarization of macrophages to develop MPE: 1. the clinical relationship among MPs, miR-375, metabolism and polarization features of macrophages and the prognosis of patients; 2. the influence of lung cancer cell-derived MPs on metabolic and polarization process of macrophages and MPE development in vitro and animal models; 3. screening and verify the target genes of miR-375 and the mechanism research on the metabolism and polarization of macrophages. This project will discuss the influences of miR-375 on macrophages and the mechanism of miR-375 on MPE progress from the view of intercellular message delivery by microparticles for the first time, which will also provide new theoretical basis and target for clinical prevention and treatment

恶性胸腔积液（MPE）是原发或转移性胸膜肿瘤恶性进展的严重表现，难以控制；“细胞间信使”微颗粒（MPs）和巨噬细胞均参与肿瘤恶性进展。我们前期临床研究发现MPE中MPs含有的miR-375显著高于良性胸水，生物信息学分析表明miR-375的下游靶基因参与代谢通路；体外也发现肺癌细胞MPs可经调控巨噬细胞代谢促其向M2型极化。.在此基础上，我们拟就微颗粒中miR-375经调控巨噬细胞代谢与极化促进MPE恶性进展的机制进行研究：1.临床水平分析MPE中MPs、miR-375、巨噬细胞代谢及表型与患者预后的关系；2.细胞和动物水平研究MPs中miR-375对巨噬细胞代谢、极化和MPE的作用；3.筛选并验证miR-375的靶基因及其影响巨噬细胞代谢和极化的作用机制。本研究首次从微颗粒在细胞间传递作用的角度探讨miR-375对巨噬细胞的影响及对MPE进展的作用及机制，为临床防治提供新的理论依据与靶点

恶性胸腔积液（MPE）是原发或转移性胸膜肿瘤恶性进展的严重表现，难以控制；“细胞间信使”微颗粒（MPs）和巨噬细胞均参与肿瘤恶性进展。通过本研究，我们发现并证实：良恶性胸腔积液中带有恶性标记的MPs、MPs中含有miRNAs的种类与数量、以及巨噬细胞的代谢与表型均显著异于良性胸水，具有与患者预后的相关性；在动物水平也证实了MPs对巨噬细胞代谢、极化及促进MPE的作用；另外对差异miRNAs预测基因的GO、KEGG功能富集分析同样提示有参与细胞外颗粒转运、细胞分化及代谢过程的靶基因存在，本研究结果强烈提示胸水上清的微颗粒中确实存在能够参与并影响巨噬细胞功能与代谢的miRNA。本研究首次从微颗粒在细胞间传递作用的角度探讨miRNAs对巨噬细胞的影响及对MPE进展的作用及机制，有望为临床防治提供新的理论依据与靶点。