耐药是胃癌化疗失败的主要原因。自噬是肿瘤细胞在化疗条件下存活的重要机制。转录因子TFEB能够调控自噬和溶酶体外排，在多种疾病中发挥重要作用，但其在肿瘤耐药中作用尚不清楚。我们通过前期研究，发现TFEB在胃癌耐药细胞系中表达升高，抑制TFEB能够增强耐药细胞的化疗敏感性，且TFEB核表达与胃癌患者预后密切相关，提示TFEB在胃癌耐药中发挥重要作用，可能是影响胃癌化疗疗效和患者生存期的关键分子。本研究拟通过体内外功能实验，阐明TFEB在胃癌耐药中发挥的作用；机制层面，阐明TFEB通过调控自噬促进胃癌耐药，并研究其通过调控LAMP1促进溶酶体外排参与胃癌耐药。此外，我们将联合应用基因芯片、iTRAQ和ChIP-Seq技术，揭示受TFEB调控的下游关键效应靶分子和信号调控网络。本项目将阐明TFEB在胃癌耐药中的作用及机制，有助于深化对肿瘤耐药的认识，为逆转胃癌耐药提供新靶点。

Chemodrug resistance is the main cause of the failure of the chemo treatment against gastric cancer. Cancer cells could confer autophagy to survive under chemotherapy, which is a crucial mechanism of chemodrug resistance. The transcription factor TFEB could induce autophagy and LAMP1 mediated lysosomal exocytosis, which has been reported to play important roles in many metabolic storage diseases. However, the role of TFEB in cancer chemodrug resistance remains elusive. We previously found that TFEB is upregulated in gastric chemodrug resistant cell lines. Inhibition of TFEB could enhance the cancer cell sensitivity to the chemodrugs. Moreover, nuclear TFEB expression is highly correlated with the poor prognosis of gastric cancer patients. All above results indicated that TFEB might play an important role in modulating chemodrug resistance of gastric cancer and it might be a crucial molecule that influence the patients’ survival time. In the current project, we aim to validate the function of TFEB in the chemodrug resistance of gastric cancer through in vitro and in vivo functional studies. To dissect the mechanism, we plan to study the impact of TFEB on autophagy as well as it’s modulation on LAMP1 mediated lysosomal exocytosis. Furthermore, we will utilize the high-throughput omics methods including microarray, iTRAQ and ChIP-Seq to identify the target molecules of TFEB and the related signaling pathways. Overall, this project will elucidate the function of TFEB in chemodrug resistance of gastric cancer and the underlying mechanisms, deepen the understanding of the mechanisms of cancer chemodrug resistance, and provide novel potential targets for reversing chemodrug resistance in gastric cancer.