胃癌外泌体lncFERO调控肿瘤干细胞脂代谢和铁死亡的研究

肿瘤干细胞是肿瘤复发与耐药的重要原因。作为一种依赖铁离子并受胞内外信号严密调控的新型细胞死亡方式，铁死亡在肿瘤干细胞中的作用值得广泛关注。甾醇辅酶A去饱和酶(SCD1)催化多不饱和脂肪酸转化为单不饱和脂肪酸，减少脂过氧化物积累，抑制铁死亡。我们预实验发现，胃癌化疗耐药相关的外泌体lncRNA(lncFERO)与SCD1表达呈正相关。胃癌外泌体lncFERO可以被胃癌干细胞摄取，与SCD1启动子结合，调控多/单不饱和脂肪酸比例。进一步发现，胃癌去泛素化酶USP7调控了lncFERO分泌。据此我们推测，胃癌细胞可通过USP7促进外泌体lncFERO释放，调控胃癌干细胞SCD1表达，抑制多不饱和脂肪酸含量和铁死亡。本课题拟从临床、体外和体内实验揭示胃癌干细胞躲避死亡的新机制，并尝试靶向lncFERO，增加胃癌干细胞铁死亡，为胃癌治疗提供新策略。

Cancer stem cells are an important cause of tumor recurrence and drug resistance. As a new type of cell death which relies on iron ions and is strictly regulated by intracellular and extracellular signals, the role of ferroptosis in tumor stem cells deserves extensive attention. Stearyl coenzyme A desaturatase 1 (SCD1) catalyzes the conversion of polyunsaturated fatty acids into monounsaturated fatty acids, inhibiting the accumulation of lipid peroxides and reducing ferroptosis. Our preliminary experiments showed that exosome lncRNA (lncFERO), which is associated with chemotherapy resistance in gastric cancer, was positively correlated with SCD1 expression. Gastric cancer exosome lncFERO could be ingested by cancer stem cells to regulate polyunsaturated/monounsaturated fatty acid ratio by binding with SCD1 promoter. It was further found that gastric cancer deubiquitination enzyme USP7 promoted the secretion of lncFERO, while lncFERO combined with SCD1 promoter in cancer stem cells. Therefore, we speculat that gastric cancer cells could promote the release of exosome lncFERO through USP7, to regulate the expression of SCD1 in gastric cancer stem cells and inhibit the content of polyunsaturated fatty acids and ferroptosis. This project intends to reveal a new mechanism of gastric cancer stem cells to escape from death by performing clinical, in vitro and in vivo experiments, and tries to target the microenvironment lncFERO to increase ferroptosis and reduce drug resistance of gastric cancer stem cells, providing new strategies for treatment.