吸烟诱导的外泌体miR-129-3p促进肺癌发生发展的机制研究

吸烟是肺癌诱因之一，且目前机制尚不清楚。课题组前期研究发现，烟草提取物处理小鼠肺上皮细胞，导致细胞外泌体miR-129-3p表达量上调，同时伴随着Hh信号通路激活。进一步发现非小细胞肺癌样本中miR-129-3p表达显著上升，并与患者生存率存在负相关。基于此，我们推断烟草诱导肺上皮细胞表达并分泌miR-129-3p，激活Hh信号通路，促进肺癌发生。在此基础上，采用小鼠模型和分子生物学技术探究烟草诱导的miR-129-3p促进肺癌发生的分子机制。①明确吸烟对外泌体miR-129-3p表达的促进效应；②基于临床数据探究外泌体miR-129-3p表达量与肺癌发生发展之间的相关性；③解析外泌体miR-129-3p促进肺癌发生发展的分子机制；④基于动物模型探究外泌体miR-129-3p对肺癌生长和转移的影响。本研究有望揭示吸烟诱导肺癌的分子机制，并为肺癌的诊治提供分子标记和药物靶点。

Lung cancer is the most fatal cancer in the world, and smoking is the cause. However, the mechanism by which smoking inducing lung cancer is still obscure. Exploring this mechanism is helpful to encourage smokers to quit smoking. Our previous studies find that the expression of exosomal miR-129-3p is apparently upregulated in mouse lung epithelial cells after treated by cigarette smoke extract (CSE), accompanied by Hh pathway hyperactivation. We further reveal that the expression of miR-129-3p is elevated in clinical non-small cell lung cancer (NSCLC) samples, and is negatively correlated with the survival of patients. Therefore, we propose our hypothesis that CSE-induced exosomal miR-129-3p promotes lung cancer tumorigenesis through activating Hh pathway. Based on these results, this project will employ mouse model and molecular biological techniques to investigate the mechanism by which CSE-induced exosomal miR-129-3p promoting lung cancer tumorigenesis. Firstly, we will validate the effect of smoking upon exosomal miR-129-3p expression in lung epithelial cells. Secondly, we will investigate the relationship between exosomal miR-129-3p levels and the occurrence and development of lung cancer using clinical data. Thirdly, we will decode the molecular mechanism of exosomal miR-129-3p regulating lung cancer tumorigenesis. Finally, we will check the effects of exosomal miR-129-3p upon lung cancer growth and metastasis through mouse model. This study is expected to reveal the molecular mechanism how smoking induces lung cancer, and also provide bio-marker and drug target for lung cancer diagnosis and clinical treatment.