肿瘤恶病质是各种恶性肿瘤患者的主要并发症，以骨骼肌与脂肪组织的消耗最为明显。外泌体在肿瘤恶病质骨骼肌与脂肪组织消耗中的参与作用日益受到重视。我们前期研究发现，恶病质性C26肿瘤细胞分泌的外泌体能够诱导体外肌肉萎缩和脂肪脂解，应用蛋白质组学与转录组学分析发现，外泌体携带的miR-195a-5p与Angptl2蛋白可能是诱导肌萎缩与脂肪脂解的效应分子。本课题拟在前期工作的基础上，以外泌体介导的信号传导为主线：①从细胞和动物水平进一步确证C26外泌体及其效应分子诱导肿瘤恶病质骨骼肌与脂肪组织消耗的作用；②寻找miR-195a-5p的靶基因和Angptl2蛋白的下游信号；③明确C26外泌体通过miR-195a-5p-smad7/sirt1/Zfp423信号通路和Angptl2-ROS信号通路诱导肌萎缩与脂解的作用，揭示C26外泌体参与肿瘤恶病质病理发展的分子机制，拓展肿瘤恶病质治疗的新思路。

Cancer cachexia is a major complication of various malignancies, accompanied with severe loss of skeletal muscle and adipose tissue. The research on the role of exosomes in muscle atrophy and lipolysis of cancer cachexia has attracted more and more interest of researchers. In our preliminary study, it was found that exosomes secreted by C26 cells (cachexia-inducing cell line) can induce muscle atrophy and lipolysis in vitro. Using proteomic analysis and transcriptomics analysis technologies, miR-195a-5p and Angptl2 were identified as possible active miRNA and protein in C26 exosomes, respectively. In the present project, based on our preliminary results, we will focus on studying the signal transduction of exosomes in cancer cachexia. Firstly, we would try to confirm the roles of C26 exosomes and its active components in inducing muscle atrophy and lipolysis using in vitro and in vivo cancer cachexia models. Secondly, the possible target genes of miR-195a-5p and possible down-stream signals of Angptl2 would be searched. Thirdly, we would try to reveal the effects of C26 exosomes in regulating miR-195a-5p-smad7/sirt1/Zfp423 and Angptl2-ROS signaling pathways which result in muscle atrophy and fat lipolysis. The aim of this project is to clarify the mechanisms of C26 exosomes in inducing cancer cachexia, and to explore new targets for the therapy of cancer cachexia.