Essential roles of exosome and circRNA_101093 on ferroptosis desensitization in lung adenocarcinoma  

作　　者：Xiao Zhang Yunhua Xu Lifang Ma Keke Yu Yongjie Niu Xin Xu Yi Shi Susu Guo Xiangfei Xue Yikun Wang Shiyu Qiu Jiangtao Cui Hong Wang Xiaoting Tian Yayou Miao Fanyu Meng Yongxia Qiao Yongchun Yu Jiayi Wang 

机构地区：[1]Department of Laboratory Medicine,Shanghai Chest Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200030,P.R.China [2]Department of Thoracic Surgery,Shanghai Chest Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200030,P.R.China [3]Shanghai Institute of Thoracic Oncology,Shanghai Chest Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200030,P.R.China [4]Shanghai Lung Cancer Center,Shanghai Chest Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200030,P.R.China [5]Department of Bio-bank,Shanghai Chest Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200030,P.R.China [6]Shanghai Municipal Hospital of Traditional Chinese Medicine,Shanghai University of Traditional Chinese Medicine,Shanghai 200071,P.R.China [7]Bio-X Institutes,Key Laboratory for the Genetics of Developmental and Neuropsychiatric disorder,Shanghai Jiao Tong University,Shanghai 200030,P.R.China [8]Department of Clinical Laboratory Medicine,Shanghai Tenth People’s Hospital of Tongji University,Shanghai 200072,P.R.China [9]School of Public Health,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,P.R.China

出　　处：《Cancer Communications》2022年第4期287-313,共27页癌症通讯（英文）

基　　金：National Natural Science Foundation of China,Grant/Award Numbers:81871907,81822029,81872288,82173015,81902315,81902869,81774291;ShanghaiMunicipal Education Commission-Gaofeng Clinical Medicine,Grant/Award Number:20191834;Project of Clinical Research Supporting System;Clinical Medicine First-class Discipline;Shanghai Municipal Education Commission and Shanghai Education Development Foundation,Grant/Award Number:18CG16;Shanghai Sailing Program,Grant/Award Number:19YF1444800;Science and technology commission of Shanghai municipality project,Grant/Award Numbers:19140902600,21140902800;Shanghai ChestHospital,Grant/Award Numbers:2018YNJCM01,2019YNJCM06,2021YNZYJ01,2021YNZYY01,2021YNZYY02。

摘　　要：Background:Resistance to ferroptosis,a regulated cell death caused by irondependent excessive accumulation of lipid peroxides,has recently been linked to lung adenocarcinoma(LUAD).Intracellular antioxidant systems are required for protection against ferroptosis.The purpose of the present studywas to investigate whether and how extracellular system desensitizes LUAD cells to ferroptosis.Methods:Established human lung fibroblasts MRC-5,WI38,and human LUAD H1650,PC9,H1975,H358,A549,and H1299 cell lines,tumor and matched normal adjacent tissues of LUAD,and plasma from healthy individuals and LUAD patients were used in this study.Immunohistochemistry and immunoblotting were used to analyze protein expression,and quantitative reverse transcription-PCR was used to analyze mRNA expression.Cell viability,cell death,and the lipid reactive oxygen species generationwere measured to evaluate the responses to ferroptosis.Exosomes were observed using transmission electron microscope.The localization of arachidonic acid(AA)was detected using click chemistry labeling followed by confocal microscopy.Interactions between RNAs and proteins were detected using RNA pull-down,RNA immunoprecipitation and photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation methods.Proteomic analysis was used to investigate RNA-regulated proteins,and metabolomic analysis was performed to analyze metabolites.Cellderived xenograft,patient-derived xenograft,cell-implanted intrapulmonary LUAD mouse models and plasma/tissue specimens from LUAD patients were used to validate the molecular mechanism.Results:Plasma exosome from LUAD patients specifically reduced lipid peroxidation and desensitized LUAD cells to ferroptosis.A potential explanation is that exosomal circRNA_101093(cir93)maintained an elevation in intracellular cir93 in LUAD to modulate AA,a poly-unsaturated fatty acid critical for ferroptosisassociated increased peroxidation in the plasma membrane.Mechanistically,cir93 interacted with and increased fatty acid-binding protei

关 键 词：EXOSOME circRNA_101093 ferroptosis DESENSITIZATION lung adenocarcinoma lipid peroxidation poly-unsaturated fatty acid TAURINE N-arachidonoyl taurine RNA-protein interaction 

分 类 号：R73[医药卫生—肿瘤]