Keap1/Nrf2/p62抗氧化通路调控细胞自噬对胰腺癌化疗敏感性的影响及其机制的研究

化疗耐药是胰腺癌临床治疗面临的最大难题之一。本课题组近期研究发现提升细胞内活性氧（ROS）水平有望克服胰腺癌化疗耐药，然而细胞内异常活化的抗氧化系统限制了ROS的抗肿瘤作用。既往研究表明Keap1/Nrf2/p62通路与自噬在细胞抗氧化过程中发挥了重要作用，但二者之间的关系以及在胰腺癌化疗耐药中的作用尚不清楚。为了进一步探讨内源性抗氧化机制与肿瘤耐药之间的关系，本项目拟研究Keap1/Nrf2/p62通路与自噬在胰腺癌中的相互作用模式，通过基因转染、RNA干扰、电镜及激光共聚焦等技术明确Keap1/Nrf2/p62通路与自噬对胰腺癌化疗敏感性的影响，通过功能分类基因芯片技术筛选Keap1/Nrf2/p62通路可能调控胰腺癌细胞自噬的关键信号分子，并阐明其作用机制。本项目将在分子水平、细胞功能及动物模型等层面展开研究，以期为寻找胰腺癌治疗的新靶点提供实验依据，并为其临床治疗开辟新的途径。

Chemoresistance is one of the biggest challenges facing the current clinical treatment of pancreatic cancer. Our recently studies found that enhance intracellular reactive oxygen species (ROS) level is expected to overcome chemoresistance of pancreatic cancer, but the abnormal activation of intracellular antioxidant system limits the antitumor effects of ROS. Previous studies have showed that the Keap1/Nrf2/p62 pathway and autophagy play an important role in the antioxidant system, but the relationship between them in drug-resistance of pancreatic cancer has not yet been clearly defined. To further explore the relationship between the endogenous antioxidant mechanism and drug resistance in pancreatic cancer, the project intends to study the mode of interaction between Keap1/Nrf2/p62 pathway and autophagy in pancreatic cancer cells. To determine the effect of Keap1/Nrf2/p62 pathway and autophagy in pancreatic cancer chemotherapy sensitivity by using gene transfection, RNA interference, electron microscopy and confocal laser scanning. To screen the key signal molecules of which the Keap1/Nrf2/p62 pathway regulating of autophagy in pancreatic cancer cells by Real-time PCR array techniques, and elucidate its mechanism. This project will be further studies at the molecular level, cellular function and animal model, in order to provide the experimental basis for the new targets as well as a new way in the treatment of pancreatic cancer.