肿瘤耐药是当前肿瘤治疗的一大瓶颈，5-FU类药物在胃癌临床治疗过程中常产生耐药但机制不清。课题组利用基因芯片发现，酸性微环境下FOXO3在调控自噬诱导的胃癌细胞耐药过程中起重要作用，Rab7是FOXO3介导自噬的主要靶基因，为此我们提出：酸性微环境下FOXO3转位入核，通过结合Rab7启动子，促进自噬效应导致胃癌细胞耐药。我们拟在分子和细胞水平上明确FOXO3通过转位入核结合Rab7启动子，并调控其转录表达；拟验证FOXO3通过调节Rab7/HOPS通路活性，介导细胞自噬调控胃癌耐药的作用机理；拟在动物模型上进一步确定FOXO3对胃癌耐药的影响；最后，拟通过临床样本分析FOXO3和胃癌耐药的关系。本研究将从酸性微环境下FOXO3介导自噬这个新视点为揭示胃癌耐药的调控机制奠定基础，为寻找有效逆转耐药靶点和个体化治疗提供新思路。

Drug-resistance is the big obstacle in current cancer treatment. 5-FU-resistance often occurrs in gastric cancer therapy, but its mechanism is not clear. Based on our gene chip results, autophage modulated by FOXO3 in acid microenvironment might be the major reason for gastric drug-resistance, and Rab7 is the key factor in the process. So, we propose that FOXO3 regulate the transcription of Rab7 by bonding with Rab7 promoter after transfer into the nucleus, and then induce drug-resistance through autophage in the acid environment. We plan to illustrate it at molecular and cellular levels. We also investigate the role and mechanism of Rab7/HOPS pathway in FOXO3 induced drug-resistance, and confirm it in animal models. Finally, the result will be verified in clinical samples. This study may clarify the mechanism of FOXO3 regulating autophage into inducing drug-resistance in acid environment, and provide another thought in reversing resistance and individualized treatment.