MicroRNA-384 radiosensitizes human non-small cell lung cancer by impairing DNA damage response and repair signaling,which is inhibited by NF-κB  

作　　者：Yanchen Sun Jing Wang Minghan Qiu Jinlin Zhao Fangdi Zou Maobin Meng Xiangli Jiang Zhiyong Yuan Zeyun Mi Zhiqiang Wu 

机构地区：[1]Department of Radiation Oncology,Tianjin Medical University Cancer Institute and Hospital,Tianjin 300060,China [2]Key Laboratory of Cancer Prevention and Therapy,National Clinical Research Center for Cancer,Tianjin's Clinical Research Center for Cancer,Tianjin 300060,China [3]Department of Chemoradiotherapy,North China University of Science and Technology Affiliated Hospital,Tangshan 063000,China [4]Department of Oncology,Tianjin Union Medical Center of Nankai University,Tianjin 300121,China [5]public Laboratory,Tianjin Medical University Cancer Institute and Hospital,Tianjin Medical University,Tianjin 300070,China [6]Department of Thoracic Medical Oncology,Tianjin Medical University Cancer Institute and Hospital,Tianjin 300060,China [7]Key Laboratory of Basic and Translational Medicine on Head&Neck Cancer,Tianjin 300060,China

出　　处：《Cancer Biology & Medicine》2024年第11期1050-1066,共17页癌症生物学与医学(英文版)

基　　金：supported by the National Natural Science Foundation of China(Grant Nos.82170758,82373085,81974364,and 82172674);the Natural Science Foundation of Tianjin Municipal Science and Technology Commission(Grant No.16JCQNJC10000);the Foundation of Tianjin Medical University Cancer Institute and Hospital(Grant No.B2211);the Science&Technology Development Fund of Tianjin Education Commission for Higher Education(Grant No.2023KJ095);the Tianjin Key Medical Discipline(Specialty)Construction Project(Grant No.TJYXZDXK-009A)。

摘　　要：Objective:Radiotherapy has achieved remarkable effects in treating non-small cell lung cancer(NSCLC).However,radioresistance remains the major obstacle to achieving good outcomes.This study aims at identifying potential targets for radiosensitizing NSCLC and elucidating the underlying mechanisms.Methods:Lentivirus-based infection and CRISPR/Cas9 technology were used to modulate the expression of microRNA-384(miR-384).Cell clonogenic formation assays and a xenograft tumor model were used to analyze radiosensitivity in NSCLC cells.Fluorescence-activated cell sorting was used to assess the cell cycle and cell death.Immunofluorescence staining,Comet assays,and homologous recombination or non-homologous end-joining I-SceI/GFP reporter assays were used to study DNA damage and repair.Western blotting and quantitative real-time polymerase chain reaction were used to identify the targets of miR-384.Chromatin immunoprecipitation and polymerase chain reaction were performed to evaluate upstream regulators of miR-384.Results:MiR-384 was downregulated in NSCLC.Overexpression of miR-384 increased the radiosensitivity of NSCLC cells in vitro and in vivo,whereas knockout of miR-384 led to radioresistance.Upregulation of miR-384 radiosensitized NSCLC cells by decreasing G2/M cell cycle arrest,inhibiting DNA damage repair,and consequently increasing cell death;miR-384 depletion had the opposite effects.Further investigation revealed that ATM,Ku70,and Ku80 were direct targets of miR-384.Moreover,miR-384 was repressed by NF-κB.Conclusions:MiR-384 is an ionizing radiation-responsive gene repressed by NF-κB.MiR-384 enhances the radiosensitivity of NSCLC cells via targeting ATM,Ku80,and Ku70,which impairs DNA damage repair.Therefore,miR-384 may serve as a novel radiosensitizer for NSCLC.

关 键 词：DAMAGE inhibited REPAIR 

分 类 号：R734.2[医药卫生—肿瘤]