ARF6/EGLN2/SCD1信号通路调控铁死亡影响胰腺癌化疗耐药的实验研究

胰腺癌容易出现化疗耐药，铁死亡是一种新型程序性细胞死亡，表现为铁依赖性的脂质过氧化物堆积，从而引起细胞的脂质过氧化损伤。近年来，铁死亡在肿瘤化疗耐药中的地位逐步被认识。.本项目以通过调控铁死亡来改善胰腺癌的化疗耐药为目的，首先发现，ARF6可以通过调控SCD1的表达影响胰腺癌的铁死亡及化疗耐药；基于质谱鉴定筛选与DNA相互作用的核因子结果，我们推测EGLN2通过抑制SCD1的表达促进铁死亡，是ARF6调控SCD1表达的中间分子；深入研究发现，ARF6能通过调控β-catenin入核影响TCF7L2的转录活性，进而影响EGLN2的表达，由此提出“ARF6/EGLN2/SCD1”这一新的信号通路。针对这一通路，我们拟进一步开展体内外和临床样本的验证及干预研究，为临床上通过调控铁死亡来改善胰腺癌的化疗耐药提供干预和预测的潜在靶点。

Pancreatic cancer is prone to chemotherapy resistance, and ferroptosis is a new type of programmed cell death, which is characterized by iron dependent accumulation of lipid peroxides, resulting in lipid peroxidation damage of cells. In recent years, the role of ferroptosis in chemotherapy resistance of tumor has been gradually recognized..The purpose of this project is to improve the chemoresistance of pancreatic cancer by regulating ferroptosis. Firstly, it is found that ARF6 can affect the ferroptosis and chemoresistance of pancreatic cancer by regulating the expression of SCD1. Based on the results of screening nuclear factors interacting with DNA by mass spectrometry, we speculate that EGLN2 can promote ferroptosis by inhibiting the expression of SCD1, which is the intermediate molecule of ARF6 regulating the expression of SCD1. In-depth study, it was found that ARF6 could affect the transcription activity of TCF7L2 and the expression of EGLN2 by regulating β-catenin entry into the nucleus, thus a new signal pathway of "ARF6/EGLN2/SCD1" was proposed. In view of this pathway, we intend to further carry out in vivo and in vitro and clinical sample validation and intervention research, so as to provide potential targets for intervention and prediction of improving chemotherapy resistance of pancreatic cancer by regulating ferroptosis.