肿瘤细胞沿气腔扩散（STAS）是肺癌独有的新转移模式，直接导致术后高复发。本课题组前期发现：转录因子叉头框C2（FOXC2）在STAS阳性肺癌中高表达，并促进肺癌细胞的上皮-间充质转化（EMT）；原癌基因c-MET为FOXC2潜在靶点，在STAS阳性样本中FOXC2和c-MET表达呈正相关。基于c-MET的生物学功能及其下游信号通路在EMT中的作用（PI3K-Akt通路等），我们推测：FOXC2通过上调c-MET表达，从而激活c-MET下游信号通路，最终促进肺癌细胞EMT并导致STAS发生。在预实验基础上，本项目拟建立过表达和低表达FOXC2肺癌细胞株，明确FOXC2在肺癌EMT中的作用；采用ChIP等技术阐明FOXC2上调c-MET促进肺癌EMT的分子机制；临床标本分析FOXC2和c-MET与STAS及复发的相关性。本项目不仅能明确STAS的分子机制，更为评估复发和精准治疗提供新思路。

Tumor spread through air spaces (STAS) is a unique and novel metastatic pattern of non-small cell lung cancer (NSCLC), and closely associated with the postoperative recurrence. Our previous results showed that forkhead box C2 (FOXC2) was overexpressed in STAS-positive NSCLC specimens, and the increased expression of FOXC2 promoted epithelial-mesenchymal transition (EMT) in lung cancer cells. The proto-oncogene c-MET was the potential target of FOXC2, because our results found that the expression of FOXC2 and c-MET had linear positive correlation in STAS-positive specimens. Based on the biological function of c-MET and the effect of its downstream signaling pathways in EMT (PI3K-Akt pathway, etc.), we proposed that FOXC2 upregulated the expression of c-MET, thus activated the downstream signaling pathways of c-MET, and finally promoted the EMT of lung cancer and led to the occurrence of STAS. In this project, lung cancer cells which transfected by lentivirus-mediated FOXC2/FOXC2 inhibitor will be used to observe the role of FOXC2 in EMT process. Moreover, chromatin immunoprecipitation technique and other methods will be used to verify whether FOXC2 directly targets the expression of c-MET thus contributing to promote EMT in NSCLC. At last, clinical samples will be tested to clarify the correlation between FOXC2 and c-MET, and their relationship with STAS and postoperative recurrence. The project will not only elucidate the specific molecular mechanism of STAS in NSCLC, but also provide the new idea for recurrence evaluation and precise treatment.