Screening of Immune-related lncRNAs in Lung Adenocarcinoma and
Establishing a Survival Prognostic Risk Prediction Model

Wenxia      Jiang; Xuyou      Zhu; Jiaqi      Bo; Jun      Ma

doi:10.2174/1386207326666230913120523

Abstract

Objective: This study aimed to improve lung adenocarcinoma (LUAD) prognosis prediction based on a signature of immune-related long non-coding RNAs (lncRNAs).

Methods: LUAD samples from the TCGA database were divided into the immunity_H group and the immunity_L group. Differentially expressed RNAs (DERs) between the two groups were identified. Optimized immune-related lncRNAs combination was obtained using LASSO Cox regression. A prognostic risk prediction (RS) model was built and further validated in the training and validation datasets. A network among lncRNAs in the RS model, their co-expressed DERs, and the related KEGG pathways were established. Critical lncRNAs were validated in LUAD tissue samples.

Results: In total, 255 DERs were obtained, and 11 immune-related lncRNAs were significantly related to prognosis. Six lncRNAs were demonstrated as an optimal combination for building the RS model, including LINC00944, LINC00930, LINC00607, LINC00582, LINC00543, and LINC00319. The KM curve and ROC curve revealed the RS model to be a reliable indicator for LUAD prognosis. LINC00944 and LINC00582 showed a co-expression relationship with the MS4A1. LINC00944, LINC00582, and MS4A1 were successfully validated in LUAD samples.

Conclusion: We have established a promising LUAD patient survival prediction model based on six immune-related lncRNAs. For LUAD patients, this prognostic model could guide personalized treatment.

« Previous Next »

Graphical Abstract

[1]
Thandra, K.C.; Barsouk, A.; Saginala, K.; Sukumar Aluru, J.; Barsouk, A. Epidemiology of lung cancer. Contemp. Oncol.,  2021, 25(1), 45-52.
 [http://dx.doi.org/10.5114/wo.2021.103829] [PMID: 33911981]

[2]
Rasheed, Z. Why is cancer becoming a global endemic today? Int. J. Health Sci.,  2020, 14(5), 1-2.
 [PMID: 32952499]

[3]
Liu, J.; Cho, S.N.; Akkanti, B.; Jin, N.; Mao, J.; Long, W.; Chen, T.; Zhang, Y.; Tang, X.; Wistub, I.I.; Creighton, C.J.; Kheradmand, F.; DeMayo, F.J. ErbB2 pathway activation upon Smad4 loss promotes lung tumor growth and metastasis. Cell Rep.,  2015, 10(9), 1599-1613.
 [http://dx.doi.org/10.1016/j.celrep.2015.02.014] [PMID: 25753424]

[4]
Tong, L.; Liu, J.; Yan, W.; Cao, W.; Shen, S.; Li, K.; Li, L.; Niu, G. RDM1 plays an oncogenic role in human lung adenocarcinoma cells. Sci. Rep.,  2018, 8(1), 11525.
 [http://dx.doi.org/10.1038/s41598-018-30071-y] [PMID: 30069034]

[5]
Succony, L.; Rassl, D.M.; Barker, A.P.; McCaughan, F.M.; Rintoul, R.C. Adenocarcinoma spectrum lesions of the lung: Detection, pathology and treatment strategies. Cancer Treat. Rev.,  2021, 99, 102237.
 [http://dx.doi.org/10.1016/j.ctrv.2021.102237] [PMID: 34182217]

[6]
Zhou, Y.; Tang, L.; Chen, Y.; Zhang, Y.; Zhuang, W. An immune panel signature predicts prognosis of lung adenocarcinoma patients and correlates with immune microenvironment. Front. Cell Dev. Biol.,  2021, 9, 797984.
 [http://dx.doi.org/10.3389/fcell.2021.797984] [PMID: 34993203]

[7]
Chen, D.; Wang, Y.; Zhang, X.; Ding, Q.; Wang, X.; Xue, Y.; Wang, W.; Mao, Y.; Chen, C.; Chen, Y. Characterization of tumor microenvironment in lung adenocarcinoma identifies immune signatures to predict clinical outcomes and therapeutic responses. Front. Oncol.,  2021, 11, 581030.
 [http://dx.doi.org/10.3389/fonc.2021.581030] [PMID: 33747907]

[8]
Zhang, L.; Xu, X.; Su, X. Noncoding RNAs in cancer immunity: Functions, regulatory mechanisms, and clinical application. Mol. Cancer,  2020, 19(1), 48.
 [http://dx.doi.org/10.1186/s12943-020-01154-0] [PMID: 32122338]

[9]
Notarte, K.I.; Senanayake, S.; Macaranas, I.; Albano, P.M.; Mundo, L.; Fennell, E.; Leoncini, L.; Murray, P. MicroRNA and other non-coding RNAs in epstein–barr virus-associated cancers. Cancers,  2021, 13(15), 3909.
 [http://dx.doi.org/10.3390/cancers13153909] [PMID: 34359809]

[10]
Li, J.; Zhang, C.; Zhang, C.; Wang, H. Construction of immune-related and prognostic lncRNA clusters and identification of their immune and genomic alterations characteristics in lung adenocarcinoma samples. Aging,  2020, 12(10), 9868-9881.
 [http://dx.doi.org/10.18632/aging.103251] [PMID: 32445554]

[11]
Yu, L.; Qiao, R.; Xu, J.; Han, B.; Zhong, R. FAM207BP, a pseudogene-derived lncRNA, facilitates proliferation, migration and invasion of lung adenocarcinoma cells and acts as an immune-related prognostic factor. Life Sci.,  2021, 268, 119022.
 [http://dx.doi.org/10.1016/j.lfs.2021.119022] [PMID: 33434533]

[12]
Zhao, S.; Jin, X.; Xu, S. [Expression of RASGRP2 in lung adenocarcinoma and its effect] on immune microenvironment]. Zhongguo Fei Ai Za Zhi,  2021, 24(6), 404-411.
 [PMID: 34157800]

[13]
Edgar, R.; Domrachev, M.; Lash, A.E. Gene expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res.,  2002, 30(1), 207-210.
 [http://dx.doi.org/10.1093/nar/30.1.207] [PMID: 11752295]

[14]
Der, S.D.; Sykes, J.; Pintilie, M.; Zhu, C.Q.; Strumpf, D.; Liu, N.; Jurisica, I.; Shepherd, F.A.; Tsao, M.S. Validation of a histology-independent prognostic gene signature for early-stage, non-small-cell lung cancer including stage IA patients. J. Thorac. Oncol.,  2014, 9(1), 59-64.
 [http://dx.doi.org/10.1097/JTO.0000000000000042] [PMID: 24305008]

[15]
Botling, J.; Edlund, K.; Lohr, M.; Hellwig, B.; Holmberg, L.; Lambe, M.; Berglund, A.; Ekman, S.; Bergqvist, M.; Pontén, F.; König, A.; Fernandes, O.; Karlsson, M.; Helenius, G.; Karlsson, C.; Rahnenführer, J.; Hengstler, J.G.; Micke, P. Biomarker discovery in non-small cell lung cancer: Integrating gene expression profiling, meta-analysis, and tissue microarray validation. Clin. Cancer Res.,  2013, 19(1), 194-204.
 [http://dx.doi.org/10.1158/1078-0432.CCR-12-1139] [PMID: 23032747]

[16]
Jabs, V.; Edlund, K.; König, H.; Grinberg, M.; Madjar, K.; Rahnenführer, J.; Ekman, S.; Bergkvist, M.; Holmberg, L.; Ickstadt, K.; Botling, J.; Hengstler, J.G.; Micke, P. Integrative analysis of genome-wide gene copy number changes and gene expression in non-small cell lung cancer. PLoS One,  2017, 12(11), e0187246.
 [http://dx.doi.org/10.1371/journal.pone.0187246] [PMID: 29112949]

[17]
Lohr, M.; Hellwig, B.; Edlund, K.; Mattsson, J.S.M.; Botling, J.; Schmidt, M.; Hengstler, J.G.; Micke, P.; Rahnenführer, J. Identification of sample annotation errors in gene expression datasets. Arch. Toxicol.,  2015, 89(12), 2265-2272.
 [http://dx.doi.org/10.1007/s00204-015-1632-4] [PMID: 26608184]

[18]
Li, B.L.; Wan, X.P. Prognostic significance of immune landscape in tumour microenvironment of endometrial cancer. J. Cell. Mol. Med.,  2020, 24(14), 7767-7777.
 [http://dx.doi.org/10.1111/jcmm.15408] [PMID: 32424934]

[19]
Hu, D.; Zhou, M.; Zhu, X. Deciphering immune-associated genes to predict survival in clear cell renal cell cancer. BioMed Res. Int.,  2019, 2019, 1-10.
 [http://dx.doi.org/10.1155/2019/2506843] [PMID: 31886185]

[20]
Ritchie, M.E.; Phipson, B.; Wu, D.; Hu, Y.; Law, C.W.; Shi, W.; Smyth, G.K. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res.,  2015, 43(7), e47.
 [http://dx.doi.org/10.1093/nar/gkv007] [PMID: 25605792]

[21]
Huang, D.W.; Sherman, B.T.; Lempicki, R.A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc.,  2009, 4(1), 44-57.
 [http://dx.doi.org/10.1038/nprot.2008.211] [PMID: 19131956]

[22]
Huang, D.W.; Sherman, B.T.; Lempicki, R.A. Bioinformatics enrichment tools: Paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res.,  2009, 37(1), 1-13.
 [http://dx.doi.org/10.1093/nar/gkn923] [PMID: 19033363]

[23]
Wang, P.; Wang, Y.; Hang, B.; Zou, X.; Mao, J.H. A novel gene expression-based prognostic scoring system to predict survival in gastric cancer. Oncotarget,  2016, 7(34), 55343-55351.
 [http://dx.doi.org/10.18632/oncotarget.10533] [PMID: 27419373]

[24]
Tibshirani, R. The lasso method for variable selection in the Cox model. Stat. Med.,  1997, 16(4), 385-395.
 [http://dx.doi.org/10.1002/(SICI)1097-0258(19970228)16:4<385::AID-SIM380>3.0.CO;2-3] [PMID: 9044528]

[25]
Goeman, J.J. L1 penalized estimation in the Cox proportional hazards model. Biom. J.,  2010, 52(1), 70-84.
 [PMID: 19937997]

[26]
Liu, X.F.; Gao, Z.M.; Wang, R.Y.; Wang, P.L.; Li, K.; Gao, S. Comparison of Billroth I, Billroth II, and Roux-en-Y reconstructions after distal gastrectomy according to functional recovery: A meta-analysis. Eur. Rev. Med. Pharmacol. Sci.,  2019, 23(17), 7532-7542.
 [PMID: 31539143]

[27]
Yu, G.; Wang, L.G.; Han, Y.; He, Q.Y. clusterProfiler: An R package for comparing biological themes among gene clusters. OMICS,  2012, 16(5), 284-287.
 [http://dx.doi.org/10.1089/omi.2011.0118] [PMID: 22455463]

[28]
Xu, Q.; Xu, H.; Deng, R.; Wang, Z.; Li, N.; Qi, Z.; Zhao, J.; Huang, W. Multi-omics analysis reveals prognostic value of tumor mutation burden in hepatocellular carcinoma. Cancer Cell Int.,  2021, 21(1), 342.
 [http://dx.doi.org/10.1186/s12935-021-02049-w] [PMID: 34217320]

[29]
Shannon, P.; Markiel, A.; Ozier, O.; Baliga, N.S.; Wang, J.T.; Ramage, D.; Amin, N.; Schwikowski, B.; Ideker, T. Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res.,  2003, 13(11), 2498-2504.
 [http://dx.doi.org/10.1101/gr.1239303] [PMID: 14597658]

[30]
Grondin, C.J.; Davis, A.P.; Wiegers, J.A.; Wiegers, T.C.; Sciaky, D.; Johnson, R.J.; Mattingly, C.J. Predicting molecular mechanisms, pathways, and health outcomes induced by Juul e-cigarette aerosol chemicals using the Comparative Toxicogenomics Database. Curr. Res. Toxicol.,  2021, 2, 272-281.
 [http://dx.doi.org/10.1016/j.crtox.2021.08.001] [PMID: 34458863]

[31]
Mouliere, F.; Chandrananda, D.; Piskorz, A.M.; Moore, E.K.; Morris, J.; Ahlborn, L.B.; Mair, R.; Goranova, T.; Marass, F.; Heider, K.; Wan, J.C.M.; Supernat, A.; Hudecova, I.; Gounaris, I.; Ros, S.; Jimenez-Linan, M.; Garcia-Corbacho, J.; Patel, K.; Østrup, O.; Murphy, S.; Eldridge, M.D.; Gale, D.; Stewart, G.D.; Burge, J.; Cooper, W.N.; van der Heijden, M.S.; Massie, C.E.; Watts, C.; Corrie, P.; Pacey, S.; Brindle, K.M.; Baird, R.D.; Mau-Sørensen, M.; Parkinson, C.A.; Smith, C.G.; Brenton, J.D.; Rosenfeld, N. Enhanced detection of circulating tumor DNA by fragment size analysis. Sci. Transl. Med.,  2018, 10(466), eaat4921.
 [http://dx.doi.org/10.1126/scitranslmed.aat4921] [PMID: 30404863]

[32]
Dang, D.K.; Park, B.H. Circulating tumor DNA: Current challenges for clinical utility. J. Clin. Invest.,  2022, 132(12), e154941.
 [http://dx.doi.org/10.1172/JCI154941] [PMID: 35703177]

[33]
Campos-Carrillo, A.; Weitzel, J.N.; Sahoo, P.; Rockne, R.; Mokhnatkin, J.V.; Murtaza, M.; Gray, S.W.; Goetz, L.; Goel, A.; Schork, N.; Slavin, T.P. Circulating tumor DNA as an early cancer detection tool. Pharmacol. Ther.,  2020, 207, 107458.
 [http://dx.doi.org/10.1016/j.pharmthera.2019.107458] [PMID: 31863816]

[34]
Beylerli, O.; Gareev, I.; Sufianov, A.; Ilyasova, T.; Guang, Y. Long noncoding RNAs as promising biomarkers in cancer. Noncoding RNA Res.,  2022, 7(2), 66-70.
 [http://dx.doi.org/10.1016/j.ncrna.2022.02.004] [PMID: 35310927]

[35]
Li, Y.; Shen, R.; Wang, A.; Zhao, J.; Zhou, J.; Zhang, W.; Zhang, R.; Zhu, J.; Liu, Z.; Huang, J. Construction of a prognostic immune-related LncRNA risk model for lung adenocarcinoma. Front. Cell Dev. Biol.,  2021, 9, 648806.
 [http://dx.doi.org/10.3389/fcell.2021.648806] [PMID: 33869203]

[36]
Wang, J.; Yin, X.; Zhang, Y.Q.; Ji, X. Identification and validation of a novel immune-related four-lncRNA signature for lung adenocarcinoma. Front. Genet.,  2021, 12, 639254.
 [http://dx.doi.org/10.3389/fgene.2021.639254] [PMID: 33708243]

[37]
Mohebi, M.; Ghafouri-Fard, S.; Modarressi, M.H.; Dashti, S.; Zekri, A.; Kholghi-Oskooei, V.; Taheri, M. Expression analysis of vimentin and the related lncRNA network in breast cancer. Exp. Mol. Pathol.,  2020, 115, 104439.
 [http://dx.doi.org/10.1016/j.yexmp.2020.104439] [PMID: 32283061]

[38]
Shen, Y.; Peng, X.; Shen, C. Identification and validation of immune-related lncRNA prognostic signature for breast cancer. Genomics,  2020, 112(3), 2640-2646.
 [http://dx.doi.org/10.1016/j.ygeno.2020.02.015] [PMID: 32087243]

[39]
Xue, Q.; Wang, Y.; Zheng, Q.; Chen, L.; Jin, Y.; Shen, X.; Li, Y. Construction of a prognostic immune-related lncRNA model and identification of the immune microenvironment in middle- or advanced-stage lung squamous carcinoma patients. Heliyon,  2022, 8(5), e09521.
 [http://dx.doi.org/10.1016/j.heliyon.2022.e09521] [PMID: 35663751]

[40]
He, B.; Pan, H.; Zheng, F.; Chen, S.; Bie, Q.; Cao, J.; Zhao, R.; Liang, J.; Wei, L.; Zeng, J.; Li, H.; Cui, X.; Ding, Y.; Chao, W.; Xiang, T.; Cheng, Y.; Qiu, G.; Huang, S.; Tang, L.; Chang, J.; Luo, D.; Yang, J.; Zhang, B. Long noncoding RNA LINC00930 promotes PFKFB3-mediated tumor glycolysis and cell proliferation in nasopharyngeal carcinoma. J. Exp. Clin. Cancer Res.,  2022, 41(1), 77.
 [http://dx.doi.org/10.1186/s13046-022-02282-9] [PMID: 35209949]

[41]
Zhang, L.; Liu, H.; Long, Y.; Zhang, Y. Overexpression of LINC00607 inhibits cell growth and aggressiveness by regulating the miR-1289/EFNA5 axis in non-small-cell lung cancer. Open Med.,  2023, 18(1), 20230649.
 [http://dx.doi.org/10.1515/med-2023-0649] [PMID: 37333453]

[42]
Gong, W.; Hong, L.; Qian, Y. Identification and experimental validation of LINC00582 Associated with B Cell immune and development of pulpitis: Bioinformatics and in vitro analysis. Diagnostics,  2023, 13(10), 1678.

[43]
Qi, G.; Kong, W.; Mou, X.; Wang, S. A new method for excavating feature lncRNA in lung adenocarcinoma based on pathway crosstalk analysis. J. Cell. Biochem.,  2019, 120(6), 9034-9046.
 [http://dx.doi.org/10.1002/jcb.28177] [PMID: 30582215]

[44]
Ji, X.; Bossé, Y.; Landi, M.T.; Gui, J.; Xiao, X.; Qian, D.; Joubert, P.; Lamontagne, M.; Li, Y.; Gorlov, I.; de Biasi, M.; Han, Y.; Gorlova, O.; Hung, R.J.; Wu, X.; McKay, J.; Zong, X.; Carreras-Torres, R.; Christiani, D.C.; Caporaso, N.; Johansson, M.; Liu, G.; Bojesen, S.E.; Le Marchand, L.; Albanes, D.; Bickeböller, H.; Aldrich, M.C.; Bush, W.S.; Tardon, A.; Rennert, G.; Chen, C.; Teare, M.D.; Field, J.K.; Kiemeney, L.A.; Lazarus, P.; Haugen, A.; Lam, S.; Schabath, M.B.; Andrew, A.S.; Shen, H.; Hong, Y.C.; Yuan, J.M.; Bertazzi, P.A.; Pesatori, A.C.; Ye, Y.; Diao, N.; Su, L.; Zhang, R.; Brhane, Y.; Leighl, N.; Johansen, J.S.; Mellemgaard, A.; Saliba, W.; Haiman, C.; Wilkens, L.; Fernandez-Somoano, A.; Fernandez-Tardon, G.; van der Heijden, E.H.F.M.; Kim, J.H.; Dai, J.; Hu, Z.; Davies, M.P.A.; Marcus, M.W.; Brunnström, H.; Manjer, J.; Melander, O.; Muller, D.C.; Overvad, K.; Trichopoulou, A.; Tumino, R.; Doherty, J.; Goodman, G.E.; Cox, A.; Taylor, F.; Woll, P.; Brüske, I.; Manz, J.; Muley, T.; Risch, A.; Rosenberger, A.; Grankvist, K.; Johansson, M.; Shepherd, F.; Tsao, M.S.; Arnold, S.M.; Haura, E.B.; Bolca, C.; Holcatova, I.; Janout, V.; Kontic, M.; Lissowska, J.; Mukeria, A.; Ognjanovic, S.; Orlowski, T.M.; Scelo, G.; Swiatkowska, B.; Zaridze, D.; Bakke, P.; Skaug, V.; Zienolddiny, S.; Duell, E.J.; Butler, L.M.; Koh, W.P.; Gao, Y.T.; Houlston, R.; McLaughlin, J.; Stevens, V.; Nickle, D.C.; Obeidat, M.; Timens, W.; Zhu, B.; Song, L.; Artigas, M.S.; Tobin, M.D.; Wain, L.V.; Gu, F.; Byun, J.; Kamal, A.; Zhu, D.; Tyndale, R.F.; Wei, W.Q.; Chanock, S.; Brennan, P.; Amos, C.I. Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk. Nat. Commun.,  2018, 9(1), 3221.
 [http://dx.doi.org/10.1038/s41467-018-05074-y] [PMID: 30104567]

[45]
Zhou, W.; Yin, M.; Cui, H.; Wang, N.; Zhao, L.L.; Yuan, L.Z.; Yang, X.P.; Ding, X.M.; Men, F.Z.; Ma, X.; Na, J.R. Identification of potential therapeutic target genes and mechanisms in non-small-cell lung carcinoma in non-smoking women based on bioinformatics analysis. Eur. Rev. Med. Pharmacol. Sci.,  2015, 19(18), 3375-3384.
 [PMID: 26439031]

[46]
Bousoik, E.; Montazeri Aliabadi, H. “Do We Know Jack” About JAK? A Closer Look at JAK/STAT Signaling Pathway. Front. Oncol.,  2018, 8, 287.
 [http://dx.doi.org/10.3389/fonc.2018.00287] [PMID: 30109213]

[47]
Templeton, A.K.; Miyamoto, S.; Babu, A.; Munshi, A.; Ramesh, R. Cancer stem cells: Progress and challenges in lung cancer. Stem Cell Investig.,  2014, 1, 9.
 [PMID: 27358855]

[48]
Mudd, T.W., Jr; Lu, C.; Klement, J.D.; Liu, K. MS4A1 expression and function in T cells in the colorectal cancer tumor microenvironment. Cell. Immunol.,  2021, 360, 104260.
 [http://dx.doi.org/10.1016/j.cellimm.2020.104260] [PMID: 33352466]

Rights & Permissions Print Cite

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/1386207326666230913120523	Print ISSN 1386-2073
Publisher Name Bentham Science Publisher	Online ISSN 1875-5402

Combinatorial Chemistry & High Throughput Screening

Screening of Immune-related lncRNAs in Lung Adenocarcinoma and Establishing a Survival Prognostic Risk Prediction Model

Abstract Play Pause

Graphical Abstract

Related Journals

Abstract