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

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外文摘要：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.

外文关键词：

Radiotherapynon-small-cell lung cancerDNA damage and repairmicroRNANF-κB

作者：

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

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作者单位：

Department of Radiation Oncology,Tianjin Medical University Cancer Institute and Hospital,Tianjin 300060,China

Key Laboratory of Cancer Prevention and Therapy,National Clinical Research Center for Cancer,Tianjin's Clinical Research Center for Cancer,Tianjin 300060,China

Department of Chemoradiotherapy,North China University of Science and Technology Affiliated Hospital,Tangshan 063000,China

Department of Oncology,Tianjin Union Medical Center of Nankai University,Tianjin 300121,China

Public Laboratory,Tianjin Medical University Cancer Institute and Hospital,Tianjin Medical University,Tianjin 300070,China

Department of Thoracic Medical Oncology,Tianjin Medical University Cancer Institute and Hospital,Tianjin 300060,China

Key Laboratory of Basic and Translational Medicine on Head&Neck Cancer,Tianjin 300060,China

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出版年：

2024

DOI：

10.20892/j.issn.2095-3941.2024.0146

癌症生物学与医学(英文版)

中国抗癌协会

癌症生物学与医学(英文版)

CSTPCD

影响因子：1.07

ISSN：2095-3941

年,卷(期)：2024.21(11)