肿瘤通过分泌MALAT1诱导脂肪棕色化的机制研究

50%-80%的癌症患者伴随恶病质，恶病质与癌症患者不良预后及高死亡率息息相关。研究发现肺癌小鼠模型中，脂肪组织发生棕色化激活，这是导致恶病质过程中负能量平衡的主要原因。然而肿瘤细胞如何影响脂肪细胞的棕色化还有待进一步研究。申请人研究发现肺癌细胞（LLC）分泌的外泌体在体外能够激活脂肪细胞，同时LLC分泌的外泌体中富含lncRNA-MALAT1，通过生物信息学预测发现MALAT1能够与miR-133结合，进而可能导致脂肪激活过程中重要的转录因子PRDM16的表达量上升。本项目拟从动物和细胞模型层面，揭示LLC细胞分泌的外泌体对脂肪细胞的激活作用；系统分析LLC细胞分泌的MALAT1在脂肪棕色化过程中起的作用；探索抑制MALAT1的表达量对恶病质的治疗效果。本研究阐明了LLC细胞通过分泌MALAT1引起脂肪棕色化从而加剧恶病质的具体分子机制，为临床治疗恶病质提供新的治疗思路与坚实的理论基础。

50%-80% of cancer patients are accompanied by the occurrence of cachexia, which is closely related to the poor prognosis and high mortality. Previous Studies found that in mouse models of lung cancer, beige and brown adipose tissue are activated, which is the main cause of the negative energy balance in the process of cachexia. However, how tumor cells affect the “browning” of adipocytes remains unknown. In our preliminary stuy, we found that exosomes secreted by lung cancer cells (LLC) can induce the “browning” of the adipocytes in vitro, and lncRNA-MALAT1 was rich in the exosomes secreted by LLC. Bioinformatics predicted that MALAT1 can bind to miR-133, and then It may lead to an increase in the expression of PRDM16, which is a critical transcriptional factor that powerfully regulates adipocyte differentiation and activation. In this proposal, combing cellular and animal model approaches, we plan to reveal the activation effects of exosomes secreted by LLC cells on adipocyts. And we also plan to systematically analyze the role of MALAT1 in the process of the “browning” of adipocytes. Finally, we plan to explore the potential therapeutic effect of MALAT1 inhibition on cachexia. Successful completion of this study will clarify the mechanism of LLC cells in “browning” of adipocyts by secreting MALAT1 to exacerbate cachexia, and provide new therapeutic schedule, and provide a solid theoretical basis for clinical therapy of cachexia.