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Aging-related signature stratifies LUAD prognosis and uncovers senescence-induced chemoresistance via NF-κB/RELA activation

文献类型：期刊论文

作者Zhu, Chengyue8,9; Dong, Ying7; Dong, Yue8,9; Shang, Xinyu5,7; Dong, Jintong4; Ge, Tingting9; Jie, Zhijun9; Li, Jia1,2,3,5,7; Zang, Yi8; Shi, Jindong6,9
刊名RESPIRATORY RESEARCH
出版日期2025-10-02
卷号26期号:1页码:16
关键词Lung adenocarcinoma Aging Cellular senescence Chemoresistance
DOI10.1186/s12931-025-03355-x
通讯作者Dong, Ying(dongying1@simm.ac.cn) ; Li, Jia(jli@simm.ac.cn) ; Zang, Yi(yzang@lglab.ac.cn) ; Shi, Jindong(shijindong@fudan.edu.cn)
英文摘要BackgroundLung adenocarcinoma (LUAD) is the most common subtype of lung cancer and a leading cause of cancer-related mortality worldwide. Aging has emerged as a significant risk factor for LUAD, with evidence suggesting that age-associated biological changes may influence prognosis. However, the underlying molecular mechanisms linking aging to tumor progression and therapy resistance are not fully understood.MethodsWe integrated transcriptomic data from LUAD cohorts to identify aging-related genes that are differentially expressed and associated with prognosis. Then Cox regression was utilized to establish an aging-related signature. Patients were stratified based on the signature, and we examined survival differences and transcription factor expression between groups. In vitro, cellular senescence was induced in A549 cells by bleomycin treatment, and subsequent changes in gene expression, transcription factor activity, and chemoresistance were assessed. Mechanistic studies included RNA interference and inhibitor treatment to investigate the dependence of chemoresistance on specific signaling pathways.ResultsA six-gene (H2AX, IGFBP1, CCL20, TFAP2A, TNFRSF11A, TNFRSF13C) aging-related signature was identified, stratifying patients into low- and high-risk groups with distinct overall survival outcomes. High-risk patients exhibited significantly poorer survival. Transcriptomic and protein analyses revealed that the transcription factor RELA was specifically upregulated in high-risk and senescent cells. Functional studies confirmed that induction of cellular senescence increased RELA expression, NF-kappa B signaling activation and conferred resistance to paclitaxel. Notably, genetic knockdown or inhibition of NF-kappa B signaling restored chemosensitivity in senescent tumor cells without reversing the senescent phenotype itself.ConclusionsThis study established a clinically relevant aging-related signature for risk stratification in LUAD and provides mechanistic insights into how aging-driven cellular senescence promotes chemoresistance through RELA/NF-kappa B pathway activation. Targeting NF-kappa B signaling may represent a promising therapeutic approach to overcome senescence-associated chemoresistance and improve outcomes for LUAD patients.
WOS关键词CELLULAR SENESCENCE ; LUNG ADENOCARCINOMA ; IDENTIFICATION ; APOPTOSIS
资助项目National Natural Science Foundation of China
WOS研究方向Respiratory System
语种英语
WOS记录号WOS:001585584700001
出版者BMC
源URL[http://119.78.100.183/handle/2S10ELR8/321585]  
专题中国科学院上海药物研究所
通讯作者Dong, Ying; Li, Jia; Zang, Yi; Shi, Jindong
作者单位1.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Peoples R China
2.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Guangzhou 528400, Guangdong, Peoples R China
3.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Hangzhou 310000, Peoples R China
4.Nanjing Tech Univ, Coll Biotechnol & Pharmaceut Engn, Nanjing 211816, Peoples R China
5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
6.Pujiang Hosp Minhang Dist, Dept Resp Med, Shanghai 201112, Peoples R China
7.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
8.Lingang Lab, Shanghai 201101, Peoples R China
9.Fudan Univ, Shanghai Peoples Hosp 5, Dept Resp & Crit Care Med, Shanghai 200240, Peoples R China
推荐引用方式
GB/T 7714		 Zhu, Chengyue,Dong, Ying,Dong, Yue,et al. Aging-related signature stratifies LUAD prognosis and uncovers senescence-induced chemoresistance via NF-κB/RELA activation[J]. RESPIRATORY RESEARCH,2025,26(1):16.
APA Zhu, Chengyue.,Dong, Ying.,Dong, Yue.,Shang, Xinyu.,Dong, Jintong.,...&Shi, Jindong.(2025).Aging-related signature stratifies LUAD prognosis and uncovers senescence-induced chemoresistance via NF-κB/RELA activation.RESPIRATORY RESEARCH,26(1),16.
MLA Zhu, Chengyue,et al."Aging-related signature stratifies LUAD prognosis and uncovers senescence-induced chemoresistance via NF-κB/RELA activation".RESPIRATORY RESEARCH 26.1(2025):16.

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来源：上海药物研究所

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