Nuclear PLD1 combined with NPM1 induces gemcitabine resistance through tumorigenic IL7R in pancreatic adenocarcinoma  

作　　者：Danqi Fu Jingrui Yan Zhaoyu Zhang Yang Liu Xiaoqing Ma Jinsheng Ding Shengyu Yang Ran Zhao Antao Chang Chuntao Gao Jing Liu Tiansuo Zhao Xiuchao Wang Chongbiao Huang Song Gao Ying Ma Bo Tang Yukuan Feng Hongwei Wang Jihui Hao 

机构地区：[1]Department of Pancreatic Cancer,Tianjin Medical University Cancer Institute and Hospital,National Clinical Research Centre for Cancer,Key Laboratory of Cancer Prevention and Therapy,Tianjin 300060,China [2]Department of General Surgery,Changzheng Hospital,Naval Medical University(Second Military Medical University),Shanghai 200003,China [3]Department of Cellular and Molecular Physiology,Penn State College of Medicine,Hershey,Pennsylvania 17033,USA

出　　处：《Cancer Biology & Medicine》2023年第8期599-626,共28页癌症生物学与医学（英文版）

基　　金：supported by the National Key Research and Development Program of China(Grant No.2021YFA1201100);the National Natural Science Foundation of China(Grant Nos.82103006,82030092,81720108028,82072657,82072716,82103003,82173295,81871968,81871978,82072691,and 82103222);the Tianjin Hygiene Healthy Science and Technology Project(Grant No.TJWJ2022MS007);the Science&Technology Development Fund of Tianjin Education Commission for Higher Education(Grant No.2020KJ141).

摘　　要：Objective:Pancreatic ductal adenocarcinoma(PDAC)is a highly malignant gastrointestinal cancer with a 5-year survival rate of only 9%.Of PDAC patients,15%-20%are eligible for radical surgery.Gemcitabine is an important chemotherapeutic agent for patients with PDAC;however,the efficacy of gemcitabine is limited due to resistance.Therefore,reducing gemcitabine resistance is essential for improving survival of patients with PDAC.Identifying the key target that determines gemcitabine resistance in PDAC and reversing gemcitabine resistance using target inhibitors in combination with gemcitabine are crucial steps in the quest to improve survival prognosis in patients with PDAC.Methods:We constructed a human genome-wide CRISPRa/dCas 9 overexpression library in PDAC cell lines to screen key targets of drug resistance based on sgRNA abundance and enrichment.Then,co-IP,ChIP,ChIP-seq,transcriptome sequencing,and qPCR were used to determine the specific mechanism by which phospholipase D1(PLD1)confers resistance to gemcitabine.Results:PLD1 combines with nucleophosmin 1(NPM1)and triggers NPM1 nuclear translocation,where NPM1 acts as a transcription factor to upregulate interleukin 7 receptor(IL7R)expression.Upon interleukin 7(IL-7)binding,IL7R activates the JAK1/STAT5 signaling pathway to increase the expression of the anti-apoptotic protein,BCL-2,and induce gemcitabine resistance.The PLD1 inhibitor,Vu0155069,targets PLD1 to induce apoptosis in gemcitabine-resistant PDAC cells.Conclusions:PLD1 is an enzyme that has a critical role in PDAC-associated gemcitabine resistance through a non-enzymatic interaction with NPM1,further promoting the downstream JAK1/STAT5/Bcl-2 pathway.Inhibiting any of the participants of this pathway can increase gemcitabine sensitivity.

关 键 词：Gemcitabine resistance pancreatic ductal adenocarcinoma phospholipase D1 nucleophosmin 1 CRISPRa library 

分 类 号：R735.9[医药卫生—肿瘤]