协同靶向食管鳞癌PAFR/DGKα/FAK蛋白复合体及其肿瘤微环境的作用机制研究

肿瘤细胞与其微环境互作介导肿瘤恶性进展。我们前期食管癌基因组研究发现多个调控细胞生长发育和肿瘤微环境的基因有遗传变异，包括PAFR、DGKα及FAK等重要促癌信号分子。我们发现：PAFR及DGKα在食管鳞癌（ESCC）中异常高表达，且与ESCC细胞中FAK结合并激活FAK；PAFR与DGKα可直接相互作用；DGKα促进多种巨噬细胞诱导细胞因子的释放。由于FAK是肿瘤细胞中调控M2型巨噬细胞（微环境重要组分）浸润关键的分子之一，因此，我们提出如下假设：PAFR、DGKα及FAK组成复合体激活FAK，募集M2型巨噬细胞，调控微环境，促进ESCC恶性进展；协同靶向PAFR/DGKα/FAK复合体和肿瘤微环境能够有效杀死食管癌肿瘤细胞。因此，本研究将首先揭示PAFR/DGKα/FAK复合体调控ESCC细胞与其微环境互作的机制，并为临床制定协同靶向癌基因与肿瘤微环境治疗ESCC的策略提供实验依据

The interaction of tumor cells and their microenvironment mediates the malignant progression of tumor. Our previous studies on esophageal cancer genome revealed that there are genetic variations in many genes regulating cell growth and development and tumor microenvironment, including PAFR, DGKα, FAK and other important tumor signal molecules. We found that: PAFR and DGKα are highly expressed in esophageal squamous cell carcinoma (ESCC), and bind to FAK and activate FAK in ESCC cells; PAFR can interact directly with DGKα; DGKα promotes the release of cytokines from multiple macrophages. FAK is one of the key molecules that regulate the infiltration of M2 macrophages (important components in microenvironment) in tumor cells. Therefore, we put forward hypothesis that PAFR, DGKα and FAK can form protein complex to activate FAK, recruit M2 macrophages, and resultantly promote the malignant progression of ESCC，synergistic targeting PAFR/DGKα/FAK complex and tumor microenvironment can effectively kill esophageal cancer cells. This study will hopefully reveal the mechanism of PAFR/DGKα/FAK complex regulating the interaction between ESCC cells and tumor microenvironment, and provide experiment evidence for formulating strategies for synergistically targeting ESCC cells and their microenvironment.