胃癌细胞对化疗药物敏感性低是胃癌预后差的主要原因，其机制复杂，涉及多个多途径。探索其可能机制对于提高化疗疗效有重要意义。项目组前期在胃癌细胞中发现并鉴定了5-FU诱导的lncRNA-RAG1，能促进自噬发生，降低胃癌细胞对5-FU的敏感性，但5-FU如何激活lncRNA-RAG1表达及lncRNA-RAG1如何调控自噬发生的机制尚不明确。本项目拟通过高通量测序、CRISPR 编辑系统、结构域特异性RNA纯化的染色质分离（dChIRP）、PDOX模型等技术，重点研究5-FU通过激活甲基转移酶降低lncRNA-RAG1表达、lncRNA-RAG1通过激活AMPK信号通路促进自噬发生的分子机制及lncRAG表达量与化疗疗效、患者生存期的相关性，阐明5-FU诱导的lncRNA-RAG1和自噬在调控肿瘤细胞化疗敏感性的重要作用和机制，具有重要的科学意义和临床意义。

It is a major reason of poor prognosis in gastric cancer patients that tumor cell is not sensitive for chemotherapy drugs. It involves complicated mechanisms and multiple pathways. Autophagy and lncRNA may play an important role to regulate tumor cells chemosensitivity. We found that 5-FU induced lncRNA-RAG1 promoted autophagy and reduced chemosensitivity in gastric cancer cells. But the mechanisms of how 5-FU induced the expression oflncRNA-RAG1 andlncRNA-RAG1 promote autophagy are still unknown. This project focuses on the molecular mechanisms of the up-regulated expression oflncRNA-RAG1 by the demethylase activated by 5-FU and the autophagy occurs promoted by AMPK signal pathway which is activated bylncRNA-RAG1. RNA-Seq, CRISPR/dCas9 interference and CRISPR/dCas9-activator systems and dChIRP are the major methods to explore above problems. To analyze the correlation between the expression of lncRNA-RAG1 to the curative effect of chemotherapy and survival time is the second aim. There are Important scientific and clinical significance to investigate the key role and mechanism of the chemosensitivity of gastric cancer cells regulated by autophagy induced by 5-FU through promoting the expression of lncRNA-RAG1.