FAP调控腹膜间皮细胞EMT促进胃癌腹膜转移的机制研究

Peritoneal metastasis of gastric cancers is a result of development of special cancer cell clones in the appropriate peritoneal microenvironment. Previous studies thought that peritoneal mesothelial cells just played a role of passive defense in peritoneal metastasis process. However, our previous studies found that EMT of peritoneal mesothelial cells could be induced by exfoliated cancer cells, and it played an important role in promoting peritoneal metastasis of gastric cancer. Simultaneously, our previous studies found that gastric cancer cells could induce mesothelial cells to express FAP, and the expression level of FAP was significantly correlated with EMT of peritoneal mesothelial cells and peritoneal metastasis of gastric cancer. Therefore, we speculated that: in the process of remodeling peritoneal microenvironment as the “soil” suitable for peritoneal metastasis by exfoliated cancer cells, FAP may be an important inducer, and it could promote peritoneal metastasis of gastric cancer by regulating epithelial-mesenchymal transition of peritoneal mesothelial cells. To test this hypothesis, we plan to investigate the role of FAP in regulating EMT of peritoneal mesothelial cells and in promoting peritoneal metastasis of gastric cancer, and to explore the molecular mechanisms, and also to investigate the role of FAP expression inhibition and its signaling pathways downstream block. The results of the present study will be valuable for further investigations of effective prevention and treatment of gastric cancer peritoneal dissemination.

腹膜转移是特殊的癌细胞克隆（种子）在适宜的腹膜微环境（土壤）孕育发展的结果。既往的研究认为在腹膜转移过程中腹膜间皮细胞只起着被动防御的作用，而我们的前期工作发现腹膜间皮细胞可被腹腔脱落癌细胞诱导发生EMT，其在促进胃癌腹膜转移形成过程中发挥了重要作用。同时，我们在前期工作中发现胃癌细胞可诱导腹膜间皮细胞表达FAP，其表达水平与腹膜间皮细胞EMT以及胃癌腹膜转移关系密切。由此我们猜测：在腹腔脱落癌细胞将腹膜微环境重塑为腹膜转移的适宜“土壤”过程中，FAP可能是一个重要的诱导因子，其可通过调控腹膜间皮细胞EMT促进胃癌腹膜转移的发生。为验证上述假设，本项目拟考察FAP对腹膜间皮细胞EMT的调控作用和对腹膜转移的促进作用，并探寻其调控作用的分子机制，同时探讨FAP表达抑制及其下游信号通路阻断对间皮细胞EMT的逆转效果和对腹膜转移的防治作用。研究结果将为有效的防治胃癌腹膜转移提供新的思路与靶点。

腹膜转移是特殊的癌细胞克隆（种子）在适宜的腹膜微环境（土壤）孕育发展的结果。既往的研究认为在腹膜转移过程中腹膜间皮细胞只起着被动防御的作用，而我们的前期工作发现腹膜间皮细胞可被腹腔脱落癌细胞诱导发生EMT，其在促进胃癌腹膜转移形成过程中发挥了重要作用。其中，FAP可能是一个重要的诱导因子，其可通过调控腹膜间皮细胞EMT促进胃癌腹膜转移的发生。.在此基础上，本项目构建了稳定表达FAP的体外腹膜间皮模型，证实了FAP对腹膜间皮细胞EMT的调控作用，并初步证明了FAP对胃癌腹膜转移的促进作用。同时课题组发现自噬相关基因SPHK1通过调控腹膜间皮细胞EMT和自噬促进胃癌腹膜转移，并发现脂类代谢相关基因LIPC可以调控Borrmann 4型胃癌的侵袭转移。本项目的研究结果将为有效的防治胃癌腹膜转移提供新的思路与靶点。.在本项目的支持下，发表SCI文章3篇，总计影响因子9.23，培养博士研究生3人。