[1]唐建军,韩春宾,纪玉龙,等.依赖于NRF2的lncRNA-mRNA共表达网络的全基因组识别及其在非小细胞肺癌进展中的作用[J].医学信息,2023,36(09):1-9,15.[doi:10.3969/j.issn.1006-1959.2023.09.001]
 TANG Jian-jun,HAN Chun-bin,JI Yu-long,et al.Genome-wide Identification of the lncRNA-mRNA Co-expression Network Dependent on NRF2 and its Role in the Progression of Non-small Cell Lung Cancer[J].Journal of Medical Information,2023,36(09):1-9,15.[doi:10.3969/j.issn.1006-1959.2023.09.001]
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依赖于NRF2的lncRNA-mRNA共表达网络的全基因组识别及其在非小细胞肺癌进展中的作用()
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医学信息[ISSN:1006-1959/CN:61-1278/R]

卷:
36卷
期数:
2023年09期
页码:
1-9,15
栏目:
生物信息学
出版日期:
2023-05-01

文章信息/Info

Title:
Genome-wide Identification of the lncRNA-mRNA Co-expression Network Dependent on NRF2 and its Role in the Progression of Non-small Cell Lung Cancer
文章编号:
1006-1959(2023)09-0001-10
作者:
唐建军韩春宾纪玉龙
(1.南昌大学第一附属医院呼吸与危重症医学科,江西 南昌 330052;2.江西省肿瘤医院胸外科,江西 南昌 330029;3.江西省肿瘤医院转化肿瘤研究重点实验室,江西 南昌 330029;4.江西省肿瘤医院病理科,江西 南昌 330029)
Author(s):
TANG Jian-junHAN Chun-binJI Yu-longet al.
(1.Department of Respiratory and Critical Care Medicine,the First Affiliated Hospital of Nanchang University,Nanchang 330052,Jiangxi,China;2.Department of Thoracic Surgery,Jiangxi Cancer Hospital,Nanchang 330029,Jiangxi,China;3.Key Laboratory of Translational Cancer Research,Jiangxi Cancer Hospital,Nanchang 330029,Jiangxi,China;4.Department of Pathology,Jiangxi Cancer Hospital,Nanchang 330029,Jiangxi,China)
关键词:
NRF2转录因子长链非编码RNA肺癌
Keywords:
NRF2Transcription factorLong noncoding RNAsLung cancer
分类号:
R734.2
DOI:
10.3969/j.issn.1006-1959.2023.09.001
文献标志码:
A
摘要:
目的 研究长链非编码 RNA(lncRNA)在mRNA和蛋白质水平上调节肺癌的发病和进展。方法 从TCGA数据库下载486例非小细胞肺癌(NSCLC)及50例正常组织样本的RNA-seq数据,通过GEO数据库提取NRF2依赖性转录组以及3组NRF2-KD肺癌A549细胞系和3组用于免疫沉淀的对照细胞和NRF2激活下的NRF2-KD和A549细胞;利用ChIP-seq数据寻找上游10 kb和下游3 kb之间的启动子相关的峰值基因;使用TopHat2改进差异基因表达,再利用edgeR软件标准识别不同表达的lncRNA;对DE lincRNA 和NRF2分别进行功能富集分析(GO、KEGG、Reactome途径);使用Cytoscape3.7.2对TCGA中550例NSCLC样本进行lncRNA-mRNA共表达分析;最后对上调和下调基因进行Kaplan-Meier生存分析。结果 RNA-seq和H3K27ac ChIP-seq 数据均来自于NRF2抑制和对照A549细胞;在含有NRF2 siRNA(NRF2-KD)的NRF2抑制A549样品中,共鉴定出3006个NRF2-DNA 结合峰,依赖于NRF2的H3K27ac沉积峰在转录起始位点(TSS)附近的10 kb区域显示出较高的比例;NRF2-KD与A549细胞中共发现742个DE lncRNA表达差异(404个上调和368个下调),DE lncRNA的基因本体富集分析表明它们可能在炎症和免疫防御中发挥作用;通过依赖于NRF2的DE mRNA和H3K27ac结合的mRNA的重叠基因富集途径确定了增强子调节的18个DE lncRNA,并识别相关mRNA和两者关系的通路,在功能上与DNA修复、细胞周期和DNA复制相关;在18个lncRNA中,发现LINC00488上调与肺癌预后不良有关。结论 lncRNA LINC00488 的表达依赖于NRF2的结合,并且LINC00488的上调与肺癌患者的不良预后有关,其可以作为治疗肺癌新的预后生物标志物和靶点。
Abstract:
Objective To study the onset and progression of lung cancer by long-chain noncoding RNA (lncRNA) at the mRNA and protein levels.Methods RNA-seq data of 486 non-small cell lung cancer (NSCLC) and 50 normal tissue samples were downloaded from the TCGA database. The NRF2-dependent transcriptome and three groups of NRF2-KD lung cancer A549 cell lines and three groups of control cells for immunoprecipitation and NRF2-KD and A549 cells activated by NRF2 were extracted from the GEO database. ChIP-seq data were used to find promoter-related peak genes between upstream 10 kb and downstream 3 kb. TopHat2 was used to improve the differential gene expression, and the edgeR software standard was used to identify different expressed lncRNAs. Functional enrichment analysis of DE lincRNA and NRF2 (GO, KEGG, Reactome pathway);Cytoscape 3.7.2 was used to analyze lncRNA-mRNA co-expression in 550 NSCLC samples from TCGA. Finally, Kaplan-Meier survival analysis was performed on up-regulated and down-regulated genes.Results Both RNA-seq and H3K27ac ChIP-seq data were derived from NRF2 inhibition and control A549 cells. A total of 3006 NRF2-DNA binding peaks were identified in NRF2 siRNA (NRF2-KD)-containing NRF2-suppressed A549 samples. The NRF2-dependent H3K27 ac deposition peak showed a high proportion in the 10 kb region near the transcription start site (TSS). A total of 742 DE lncRNA expression differences (404 up-regulated and 368 down-regulated) were found between NRF2-KD and A549 cells. Gene ontology enrichment analysis of DE lncRNAs showed that they might play a role in inflammation and immune defense. Through the overlapping gene enrichment pathway of NRF2-dependent DE mRNA and H3K27ac-binding mRNA, 18 enhancer-regulated DE lncRNAs were identified, and related mRNAs and pathways were identified, which were functionally related to DNA repair, cell cycle and DNA replication. Among the 18 lncRNAs, up-regulation of LINC00488 was associated with poor prognosis of lung cancer.Conclusion The expression of lncRNA LINC00488 depends on the binding of NRF2, and the up-regulation of LINC00488 is related to the poor prognosis of lung cancer patients, which can be used as a new prognostic biomarker and target for the treatment of lung cancer.

参考文献/References:

[1]Chen Z,Fillmore CM,Hammerman PS,et al.Non-small-cell lung cancers: a heterogeneous set of diseases[J].Nat Rev Cancer,2014,14(8):535-546.[2]Inamura K.Lung Cancer: Understanding Its Molecular Pathology and the 2015 WHO Classification[J].Front Oncol,2017,7:193.[3]Oberndorfer F,Müllauer L.Molecular pathology of lung cancer: current status and perspectives[J].Curr Opin Oncol,2018,30(2):69-76.[4]Ruiz-Cordero R,Devine WP.Targeted Therapy and Checkpoint Immunotherapy in Lung Cancer[J].Surg Pathol Clin,2020,13(1):17-33.[5]Zhang DD.Mechanistic studies of the NRF2-Keap1 signaling pathway[J].Drug Metab Rev,2006,38(4):769-789.[6]Hammad A,Namani A,Elshaer M,et al."NRF2 addiction" in lung cancer cells and its impact on cancer therapy[J].Cancer Lett,2019,467:40-49.[7]Wilusz JE,Sunwoo H,Spector DL.Long noncoding RNAs: functional surprises from the RNA world[J].Genes Dev,2009,23(13):1494-1504.[8]Wang Z,Song L,Ye Y,et al.Long Noncoding RNA DIO3OS Hinders Cell Malignant Behaviors of Hepatocellular Carcinoma Cells Through the microRNA-328/Hhip Axis[J].Cancer Manag Res,2020,12:3903-3914.[9]Lee JH,Khor TO,Shu L,et al.Dietary phytochemicals and cancer prevention: NRF2 signaling, epigenetics, and cell death mechanisms in blocking cancer initiation and progression[J].Pharmacol Ther,2013,137(2):153-171.[10]Kwak MK,Kensler TW.Targeting NRF2 signaling for cancer chemoprevention[J].Toxicol Appl Pharmacol,2010,244(1):66-76.[11]Yamamoto M,Kensler TW,Motohashi H.The KEAP1-NRF2 System: a Thiol-Based Sensor-Effector Apparatus for Maintaining Redox Homeostasis[J].Physiol Rev,2018,98(3):1169-1203.[12]Iyer MK,Niknafs YS,Malik R,et al.The landscape of long noncoding RNAs in the human transcriptome[J].Nat Genet,2015,47(3):199-208.[13]Kensler TW,Wakabayashi N.NRF2: friend or foe for chemoprevention?[J].Carcinogenesis,2010,31(1):90-99.[14]Zeng Z,Wang ZY,Li YK,et al.Nuclear factor erythroid 2 (NF-E2)-related factor 2 (NRF2) in non-small cell lung cancer[J].Life Sci,2020,254:117325.[15]Rangasamy T,Cho CY,Thimmulappa RK,et al.Genetic ablation of NRF2 enhances susceptibility to cigarette smoke-induced emphysema in mice[J].J Clin Invest,2004,114(9):1248-1259.[16]Cho HY,Reddy SP,Debiase A,et al.Gene expression profiling of NRF2-mediated protection against oxidative injury[J].Free Radic Biol Med,2005,38(3):325-343.[17]Cho HY,Imani F,Miller-DeGraff L,et al.Antiviral activity of NRF2 in a murine model of respiratory syncytial virus disease[J].Am J Respir Crit Care Med,2009,179(2):138-150.[18]Luo P,Wu S,Ji K,et al.LncRNA MIR4435-2HG mediates cisplatin resistance in HCT116 cells by regulating NRF2 and HO-1[J].PLoS One,2020,15(11):e0223035.[19]Zhang L,Xu X,Su X.Noncoding RNAs in cancer immunity: functions, regulatory mechanisms, and clinical application[J].Mol Cancer,2020,19(1):48.[20]Zhang G,Lan Y,Xie A,et al.Comprehensive analysis of long noncoding RNA (lncRNA)-chromatin interactions reveals lncRNA functions dependent on binding diverse regulatory elements[J].J Biol Chem,2019,294(43):15613-15622.[21]Ponjavic J,Ponting CP,Lunter G.Functionality or transcriptional noise? Evidence for selection within long noncoding RNAs[J].Genome Res,2007,17(5):556-565.[22]Hombach S,Kretz M.Non-coding RNAs:Classification, Biology and Functioning[J].Adv Exp Med Biol,2016,937:3-17.[23]Chikara S,Nagaprashantha LD,Singhal J,et al.Oxidative stress and dietary phytochemicals: Role in cancer chemoprevention and treatment[J].Cancer Lett,2018,413:122-134.[24]Bhattacharjee S,Li J,Dashwood RH.Emerging crosstalk between long non-coding RNAs and NRF2 signaling[J].Cancer Lett,2020,490:154-164.[25]Kim D,Pertea G,Trapnell C,et al.TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions[J].Genome Biol,2013,14(4):R36.[26]Robinson MD,McCarthy DJ,Smyth GK.edgeR: a Bioconductor package for differential expression analysis of digital gene expression data[J].Bioinformatics,2010,26(1):139-140.[27]Liu Y,Sun Y,Li Y,et al.Analyses of Long Non-Coding RNA and mRNA profiling using RNA sequencing in chicken testis with extreme sperm motility[J].Sci Rep,2017,7(1):9055.[28]Trapnell C,Roberts A,Goff L,et al.Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks[J].Nat Protoc,2012,7(3):562-578.[29]Xie C,Mao X,Huang J,et al.KOBAS 2.0: a web server for annotation and identification of enriched pathways and diseases[J].Nucleic Acids Res,2011,39(Web Server issue):W316-W322.[30]Ye R,Tang R,Gan S,et al.New insights into long non-coding RNAs in non-small cell lung cancer[J].Biomed Pharmacother,2020,131:110775.[31]Yoshimizu T,Miroglio A,Ripoche MA,et al.The H19 locus acts in vivo as a tumor suppressor[J].Proc Natl Acad Sci U S A,2008,105(34):12417-12422.[32]Kim K,Jutooru I,Chadalapaka G,et al.HOTAIR is a negative prognostic factor and exhibits pro-oncogenic activity in pancreatic cancer[J].Oncogene,2013,32(13):1616-1625.[33]Zhou Y,Zhang X,Klibanski A.MEG3 noncoding RNA: a tumor suppressor[J].J Mol Endocrinol,2012,48(3):R45-R53.[34]Sekine H,Motohashi H.Roles of CNC Transcription Factors NRF1 and NRF2 in Cancer[J].Cancers (Basel),2021,13(3):541.[35]Rojo de la Vega M,Chapman E,Zhang DD.NRF2 and the Hallmarks of Cancer[J].Cancer Cell,2018,34(1):21-43.[36]Menegon S,Columbano A,Giordano S.The Dual Roles of NRF2 in Cancer[J].Trends Mol Med,2016,22(7):578-593.[37]Taguchi K,Motohashi H,Yamamoto M.Molecular mechanisms of the Keap1-NRF2 pathway in stress response and cancer evolution[J].Genes Cells,2011,16(2):123-140.[38]Fernandes JCR,Acuna SM,Aoki JI,et al.Long Non-Coding RNAs in the Regulation of Gene Expression: Physiology and Disease[J].Noncoding RNA,2019,5(1):17.[39]Wu S,Lu H,Bai Y.NRF2 in cancers: A double-edged sword[J].Cancer Med,2019,8(5):2252-2267.[40]Fabrizio FP,Sparaneo A,Trombetta D,et al.Epigenetic versus Genetic Deregulation of the KEAP1/NRF2 Axis in Solid Tumors: Focus on Methylation and Noncoding RNAs[J].Oxid Med Cell Longev,2018,2018:2492063.[41]Cloer EW,Goldfarb D,Schrank TP,et al.NRF2 Activation in Cancer: From DNA to Protein[J].Cancer Res,2019,79(5):889-898.[42]Yang G,Yin H,Lin F,et al.Long noncoding RNA TUG1 regulates prostate cancer cell proliferation, invasion and migration via the NRF2 signaling axis[J].Pathol Res Pract,2020,216(4):152851.[43]Thai P,Statt S,Chen CH,et al.Characterization of a novel long noncoding RNA, SCAL1, induced by cigarette smoke and elevated in lung cancer cell lines[J].Am J Respir Cell Mol Biol,2013,49(2):204-211.[44]Moreno Leon L,Gautier M,Allan R,et al.The nuclear hypoxia-regulated NLUCAT1 long non-coding RNA contributes to an aggressive phenotype in lung adenocarcinoma through regulation of oxidative stress[J].Oncogene,2019,38(46):7146-7165.[45]Hayes JD,McMahon M,Chowdhry S,et al.Cancer chemoprevention mechanisms mediated through the Keap1-NRF2 pathway[J].Antioxid Redox Signal,2010,13(11):1713-1748.[46]Kong Q,Deng H,Li C,et al.Sustained high expression of NRF2 and its target genes induces dysregulation of cellular proliferation and apoptosis is associated with arsenite-induced malignant transformation of human bronchial epithelial cells[J].Sci Total Environ,2021,756:143840.[47]Xie F,Li L,Luo Y,et al.Long non-coding RNA LINC00488 facilitates thyroid cancer cell progression through miR-376a-3p/PON2[J].Biosci Rep,2021,41(3):BSR20201603.[48]Xu H,Ye Y.LINC00488 stimulates the progression of esophageal cancer by targeting microRNA-485-5p[J].Oncol Lett,2021,21(2):86.

更新日期/Last Update: 1900-01-01