CYS1调控RAB14介导的外泌体SGK3分泌促进胃癌腹膜转移的机制研究

胃癌腹膜转移严重影响患者生存，治疗效果差的主要原因是其机制有许多不明之处。我们通过生物信息学分析找到新的腹膜转移相关因子CYS1。原创性研究证实CYS1在胃癌中高表达，沉默CYS1抑制胃癌腹膜转移；表达谱芯片筛选发现CYS1上调RAB14，且二者结合，增强胃癌细胞外泌体分泌。CYS1上调AP-2A，AP-2A与RAB14启动子存在结合位点。RAB14促进携带SGK3的外泌体分泌，诱导腹膜间皮细胞（PMCs）发生间皮-间充质转化为癌相关成纤维细胞（CAFs），促进胃癌腹膜转移。本研究旨在证明胃癌细胞内CYS1通过调控转录因子AP-2A上调RAB14，增强RAB14介导的外泌体分泌及对SGK3向外泌体分选；另一方面，外泌体SGK3通过激活PMCs的GSK3β/β-catenin通路，诱导PMCs向CAFs转化，促进胃癌腹膜转移。研究结果将为揭示胃癌腹膜转移机制，制定新的治疗策略提供新依据。

Peritoneal metastasis affects the survival of patients with gastric cancer seriously. The main reason for the poor therapeutic effect is that the mechanism is unclear. By bioinformatics analysis, we found a new peritoneal metastasis-related factor, CYS1. The original study confirmed that the expression of CYS1 was significantly higher in gastric cancer tissues than in normal tissues, and silencing the expression of CYS1 in gastric cancer cells inhibited peritoneal metastasis of gastric cancer; the analysis of microarray showed that CYS1 upregulated RAB14, and the combination of CYS1 and RAB14 enhanced the secretion of exosomes in gastric cancer cells. CYS1 upregulated the expression of AP-2A, and seven sites in RAB14 promoter were predicted to bind AP-2A. RAB14 promoted the secretion of SGK3-carrying exosomes, then induced mesothelial mesenchymal transition of peritoneal mesothelial cells (PMCs) into cancer-related fibroblasts (CAFs), which faciliated peritoneal metastasis of gastric cancer cells. The purpose of this study was to demonstrate that CYS1 upregulates RAB14 by regulating the transcription factor AP-2A, which enhances RAB14 mediated secretion of exosomes and sorting of SGK3 into exosomes in gastric cancer cells; on the other hand, exosomal SGK3 induces PMCs to transform into CAFs and promotes peritoneal metastasis of gastric cancer by activating GSK3 β / β - catenin pathway in PMCs. The results will provide a new basis for revealing the mechanism of gastric cancer peritoneal metastasis and developing new treatment strategies.