非小细胞肺癌侵袭转移机制的研究：Caspase-8的全新非凋亡功能？

非小细胞肺癌（NSCLC）的高侵袭性是制约其预后的主要因素，其调控机制不明。Caspase-8具有重要的凋亡启动作用，前期研究发现Caspase-8能够被c-Src磷酸化，而Caspase-8的存在能够促进c-Src的活化，介导上皮间质转化的发生，在裸鼠皮下移植瘤模型中，Caspase-8和c-Src共同存在有效促进了NSCLC的侵袭转移。所以，我们推测：Caspase-8和c-Src之间的相互作用可能在NSCLC中发挥着"凋亡-侵袭"的开关作用。我们将通过体内外实验对Caspase-8和c-Src在NSCLC发生发展中的影响进行探索，在组织及细胞水平，应用分子生物学实验方法研究Caspase-8-c-Src促NSCLC侵袭转移的信号通路及其在时间和空间上的相互作用方式。项目的完成，将探明Caspase-8-c-Src的"凋亡-侵袭"开关作用的全新机制，为NSCLC侵袭转移的控制提供新思路

Non-small cell lung cancer (NSCLC), up to 75-80% of new cases of lung cancer in 2013, is a leading cause of tumor-related deaths. The aggressiveness of NSCLC is ascribed to be a poor prognosticator for overall survival in patients with NSCLC. To the date, the mechanism underlying the metastasis of NSCLC remains unclear. On the basis of our preliminary studies, Caspase-8 was phosphorylated on the site of tyrosine 380 by c-Src kinase, which in turn promoted the c-Src activation to induce the epithelial-mesenchymal transition (EMT). We observed that Caspase-8 and c-Src synergistically enhanced the metastasis of NSCLC cells in nude mice model. According to our studies and previous literature reports, we hypothesize that interaction between Caspase-8 and c-Src increases the c-Src activity to induce EMT phenotype, and consequently give a rise to NSCLC metastasis. Accordingly, we plan to conduct the research on the effects of Caspase-8-c-Src interaction on the NSCLC progression, and to disclose a novel molecular mechanisem by which Caspase-8 temporospatially increases the metastasis and the aggressiveness of NSCLC in a c-Src-dependent manner. This project is expected to uncover a novel switch "apoptosis-invasion" on the basis of Caspase-8-c-Src, and to provide a theoretical screen for a novelty anti-metastasis target.