Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
European Journal of Medical Research
Published in: European Journal of Medical Research 1/2023

Open Access 01-12-2023 | Lung Cancer | Research

Identification of molecular subgroups and establishment of risk model based on the response to oxidative stress to predict overall survival of patients with lung adenocarcinoma

Authors: Linzhuang Liu, Qinghua Hou, Baorong Chen, Xiyi Lai, Hanwen Wang, Haozhen Liu, Liusheng Wu, Sheng Liu, Kelin Luo, Jixian Liu

Published in: European Journal of Medical Research | Issue 1/2023

Login to get access

Abstract

Objective

Oxidative stress is associated with the occurrence and development of lung cancer. However, the specific association between lung cancer and oxidative stress is unclear. This study aimed to investigate the role of oxidative stress in the progression and prognosis of lung adenocarcinoma (LUAD).

Methods

The gene expression profiles and corresponding clinical information were collected from GEO and TCGA databases. Differentially expressed oxidative stress-related genes (OSRGs) were identified between normal and tumor samples. Consensus clustering was applied to identify oxidative stress-related molecular subgroups. Functional enrichment analysis, GSEA, and GSVA were performed to investigate the potential mechanisms. xCell was used to assess the immune status of the subgroups. A risk model was developed by the LASSO algorithm and validated using TCGA-LUAD, GSE13213, and GSE30219 datasets.

Results

A total of 40 differentially expressed OSRGs and two oxidative stress-associated subgroups were identified. Enrichment analysis revealed that cell cycle-, inflammation- and oxidative stress-related pathways varied significantly in the two subgroups. Furthermore, a risk model was developed and validated based on the OSRGs, and findings indicated that the risk model exhibits good prediction and diagnosis values for LUAD patients.

Conclusion

The risk model based on the oxidative stress could act as an effective prognostic tool for LUAD patients. Our findings provided novel genetic biomarkers for prognosis prediction and personalized clinical treatment for LUAD patients.
Appendix
Available only for authorised users
Literature
1.
Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics: 2020 GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49.PubMed
2.
Hutchinson BD, Shroff GS, Truong MT, Ko JP. Spectrum of lung adenocarcinoma. Semin Ultrasound CT MR. 2019;40(3):255–64.PubMed
3.
Shukla S, Evans JR, Malik R, et al. Development of a RNA-seq based prognostic signature in lung adenocarcinoma. J Natl Cancer Inst. 2017;109(1):djw200.PubMed
4.
Miller KD, Nogueira L, Devasia T, et al. Cancer treatment and survivorship statistics, 2022. CA Cancer J Clin. 2022;72(5):409–36.PubMed
5.
6.
Bronte G, Rizzo S, La Paglia L, et al. Driver mutations and differential sensitivity to targeted therapies: a new approach to the treatment of lung adenocarcinoma. Cancer Treat Rev. 2010;36(Suppl 3):S21–9.PubMed
7.
Saito M, Suzuki H, Kono K, Takenoshita S, Kohno T. Treatment of lung adenocarcinoma by molecular-targeted therapy and immunotherapy. Surg Today. 2018;48(1):1–8.PubMed
8.
Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28(19):3167–75.PubMedPubMedCentral
9.
Klaunig JE. Oxidative stress and cancer. Curr Pharm Des. 2018;24(40):4771–8.PubMed
10.
Obrador E, Liu-Smith F, Dellinger RW, et al. Oxidative stress and antioxidants in the pathophysiology of malignant melanoma. Biol Chem. 2019;400(5):589–612.PubMed
11.
Wang JY, Liu GZ, Wilmott JS, et al. Skp2-mediated stabilization of MTH1 promotes survival of melanoma cells upon oxidative stress. Cancer Res. 2017;77(22):6226–39.PubMed
12.
Nourazarian AR, Kangari P, Salmaninejad A. Roles of oxidative stress in the development and progression of breast cancer. Asian Pac J Cancer Prev. 2014;15(12):4745–51.PubMed
13.
Kruk J, Aboul-Enein HY. Reactive oxygen and nitrogen species in carcinogenesis: implications of oxidative stress on the progression and development of several cancer types. Mini Rev Med Chem. 2017;17(11):904–19.PubMed
14.
Lee JD, Cai Q, Shu XO, Nechuta SJ. The role of biomarkers of oxidative stress in breast cancer risk and prognosis: a systematic review of the epidemiologic literature. J Womens Health (Larchmt). 2017;26(5):467–82.PubMed
15.
Boakye D, Jansen L, Schöttker B, et al. Blood markers of oxidative stress are strongly associated with poorer prognosis in colorectal cancer patients. Int J Cancer. 2020;147(9):2373–86.PubMed
16.
Wu Z, Wang L, Wen Z, Yao J. Integrated analysis identifies oxidative stress genes associated with progression and prognosis in gastric cancer. Sci Rep. 2021;11(1):3292.PubMedPubMedCentral
17.
Ortega MA, Fraile-Martinez O, Pekarek L, et al. Oxidative stress markers are associated with a poor prognosis in patients with pancreatic CANCER. Antioxidants. 2022;11(4):759.PubMedPubMedCentral
18.
Caliri AW, Tommasi S, Besaratinia A. Relationships among smoking, oxidative stress, inflammation, macromolecular damage, and cancer. Mutat Res Rev Mutat Res. 2021;787:108365.PubMed
19.
Goldkorn T, Filosto S, Chung S. Lung injury and lung cancer caused by cigarette smoke-induced oxidative stress: molecular mechanisms and therapeutic opportunities involving the ceramide-generating machinery and epidermal growth factor receptor. Antioxid Redox Signal. 2014;21(15):2149–74.PubMedPubMedCentral
20.
Valavanidis A, Vlachogianni T, Fiotakis K, Loridas S. Pulmonary oxidative stress, inflammation and cancer: respirable particulate matter, fibrous dusts and ozone as major causes of lung carcinogenesis through reactive oxygen species mechanisms. Int J Environ Res Public Health. 2013;10(9):3886–907.PubMedPubMedCentral
21.
Singh B, Patwardhan RS, Jayakumar S, Sharma D, Sandur SK. Oxidative stress associated metabolic adaptations regulate radioresistance in human lung cancer cells. J Photochem Photobiol B. 2020;213:112080.PubMed
22.
Sun X, Huang X, Sun X, et al. Oxidative stress-related lncRNAs are potential biomarkers for predicting prognosis and immune responses in patients with LUAD. Front Genet. 2022;13:909797.PubMedPubMedCentral
23.
Zhang Z, Liu X, Cheng D, et al. Unfolded protein response-related signature associates with the immune microenvironment and prognostic prediction in osteosarcoma. Front Genet. 2022;13:911346.PubMedPubMedCentral
24.
Qian H, Lei T, Hu Y, Lei P. Expression of lipid-metabolism genes is correlated with immune microenvironment and predicts prognosis in osteosarcoma. Front Cell Dev Biol. 2021;9:673827.PubMedPubMedCentral
25.
Xu M, Lu JH, Zhong YZ, et al. Immunogenic cell death-relevant damage-associated molecular patterns and sensing receptors in triple-negative breast cancer molecular subtypes and implications for immunotherapy. Front Oncol. 2022;12:870914.PubMedPubMedCentral
26.
Davis S, Meltzer PS. GEOquery: a bridge between the gene expression omnibus (GEO) and bioconductor. Bioinformatics. 2007;23(14):1846–7.PubMed
27.
Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012;16(5):284–7.PubMedPubMedCentral
28.
Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26(1):139–40.PubMed
29.
Cookson SJ, Clemente Moreno MJ, Hevin C, et al. Graft union formation in grapevine induces transcriptional changes related to cell wall modification, wounding, hormone signalling, and secondary metabolism. J Exp Bot. 2013;64(10):2997–3008.PubMedPubMedCentral
30.
Gu Z, Eils R, Schlesner M. Complex heatmaps reveal patterns and correlations in multidimensional genomic data. Bioinformatics. 2016;32(18):2847–9.PubMed
31.
Wilkerson MD, Hayes DN. ConsensusClusterPlus: a class discovery tool with confidence assessments and item tracking. Bioinformatics. 2010;26(12):1572–3.PubMedPubMedCentral
32.
Aran D. Cell-type enrichment analysis of bulk transcriptomes using xCell. Methods Mol Biol. 2020;2120:263–76.PubMed
33.
Zhou Y, Zhou B, Pache L, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019;10(1):1523.PubMedPubMedCentral
34.
Ferreira MR, Santos GA, Biagi CA, Silva Junior WA, Zambuzzi WF. GSVA score reveals molecular signatures from transcriptomes for biomaterials comparison. J Biomed Mater Res A. 2021;109(6):1004–14.PubMed
35.
He F, Chen Z, Deng W, et al. Development and validation of a novel ferroptosis-related gene signature for predicting prognosis and immune microenvironment in head and neck squamous cell carcinoma. Int Immunopharmacol. 2021;98:107789.PubMed
36.
Bade BC, Dela Cruz CS. Lung cancer 2020: epidemiology, etiology, and prevention. Clin Chest Med. 2020;41(1):1–24.PubMed
37.
Lin W, Chen Y, Wu B, Chen Y, Li Z. Identification of the pyroptosis-related prognostic gene signature and the associated regulation axis in lung adenocarcinoma. Cell Death Discov. 2021;7(1):161.PubMedPubMedCentral
38.
Lu L, Liu LP, Zhao QQ, Gui R, Zhao QY. Identification of a ferroptosis-related LncRNA signature as a novel prognosis model for lung adenocarcinoma. Front Oncol. 2021;11:675545.PubMedPubMedCentral
39.
Wang Q, Li M, Yang M, et al. Analysis of immune-related signatures of lung adenocarcinoma identified two distinct subtypes: implications for immune checkpoint blockade therapy. Aging. 2020;12(4):3312–39.PubMedPubMedCentral
40.
Zhou H, Zheng M, Shi M, et al. Characteristic of molecular subtypes in lung adenocarcinoma based on m6A RNA methylation modification and immune microenvironment. BMC Cancer. 2021;21(1):938.PubMedPubMedCentral
41.
Ding XL, Su YG, Yu L, et al. Clinical characteristics and patient outcomes of molecular subtypes of small cell lung cancer (SCLC). World J Surg Oncol. 2022;20(1):54.PubMedPubMedCentral
42.
Hybertson BM, Gao B, Bose SK, McCord JM. Oxidative stress in health and disease: the therapeutic potential of Nrf2 activation. Mol Aspects Med. 2011;32(4–6):234–46.PubMed
43.
Forman HJ, Zhang H. Targeting oxidative stress in disease: promise and limitations of antioxidant therapy. Nat Rev Drug Discov. 2021;20(9):689–709.PubMedPubMedCentral
44.
Forcados GE, James DB, Sallau AB, Muhammad A, Mabeta P. Oxidative stress and carcinogenesis: potential of phytochemicals in breast cancer therapy. Nutr Cancer. 2017;69(3):365–74.PubMed
45.
Ciccarone F, Castelli S, Ciriolo MR. Oxidative stress-driven autophagy acROSs onset and therapeutic outcome in hepatocellular carcinoma. Oxid Med Cell Longev. 2019;2019:6050123.PubMedPubMedCentral
46.
Cao Y, Deng S, Yan L, et al. An oxidative stress index-based score for prognostic prediction in colorectal cancer patients undergoing surgery. Oxid Med Cell Longev. 2021;2021:6693707.PubMedPubMedCentral
47.
Kotsafti A, Scarpa M, Castagliuolo I, Scarpa M. Reactive oxygen species and antitumor immunity-from surveillance to evasion. Cancers. 2020;12(7):1748.PubMedPubMedCentral
48.
Valacchi G, Virgili F, Cervellati C, Pecorelli A. OxInflammation: from subclinical condition to pathological biomarker. Front Physiol. 2018;9:858.PubMedPubMedCentral
49.
Kennel KB, Greten FR. Immune cell—produced ROS and their impact on tumor growth and metastasis. Redox Biol. 2021;42:101891.PubMedCentral
50.
Marchi S, Guilbaud E, Tait SWG, Yamazaki T, Galluzzi L. Mitochondrial control of inflammation. Nat Rev Immunol. 2023;23(3):159–73.PubMed
51.
Weinberg SE, Singer BD, Steinert EM, et al. Mitochondrial complex III is essential for suppressive function of regulatory T cells. Nature. 2019;565(7740):495–9.PubMedPubMedCentral
52.
Aboelella NS, Brandle C, Kim T, Ding ZC, Zhou G. Oxidative stress in the tumor microenvironment and its relevance to cancer immunotherapy. Cancers. 2021;13(5):986.PubMedPubMedCentral
53.
Kuo CL, Ponneri Babuharisankar A, Lin YC, et al. Mitochondrial oxidative stress in the tumor microenvironment and cancer immunoescape: foe or friend? J Biomed Sci. 2022;29(1):74.PubMedPubMedCentral
54.
Maj T, Wang W, Crespo J, et al. Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor. Nat Immunol. 2017;18(12):1332–41.PubMedPubMedCentral
55.
Weinberg SE, Sena LA, Chandel NS. Mitochondria in the regulation of innate and adaptive immunity. Immunity. 2015;42(3):406–17.PubMedPubMedCentral
56.
Kuo CL, Chou HY, Chiu YC, et al. Mitochondrial oxidative stress by Lon-PYCR1 maintains an immunosuppressive tumor microenvironment that promotes cancer progression and metastasis. Cancer Lett. 2020;474:138–50.PubMed
57.
Cao Z, Wu W, Wei H, et al. Downregulation of histone-lysine N-methyltransferase EZH2 inhibits cell viability and enhances chemosensitivity in lung cancer cells. Oncol Lett. 2021;21(1):26.PubMed
58.
Kosibaty Z, Murata Y, Minami Y, Noguchi M, Sakamoto N. ECT2 promotes lung adenocarcinoma progression through extracellular matrix dynamics and focal adhesion signaling. Cancer Sci. 2021;112(2):703–14.PubMed
59.
Jin Z, Zhang G, Liu Y, et al. The suppressive role of HYAL1 and HYAL2 in the metastasis of colorectal cancer. J Gastroenterol Hepatol. 2019;34(10):1766–76.PubMed
60.
Wang K, Wang J, Wei F, et al. Expression of TLR4 in non-small cell lung cancer is associated with PD-L1 and poor prognosis in patients receiving pulmonectomy. Front Immunol. 2017;8:456.PubMedPubMedCentral
61.
Zhang J, Liu Y, Guo Y, Zhao Q. GPX8 promotes migration and invasion by regulating epithelial characteristics in non-small cell lung cancer. Thoracic cancer. 2020;11(11):3299–308.PubMedPubMedCentral
62.
Liu Y, Pandey PR, Sharma S, et al. ID2 and GJB2 promote early-stage breast cancer progression by regulating cancer stemness. Breast Cancer Res Treat. 2019;175(1):77–90.PubMedPubMedCentral
63.
Huang Z, Shen G, Gao J. CDK1 promotes the stemness of lung cancer cells through interacting with Sox2. Clin Transl Oncol. 2021;23(9):1743–51.PubMed
64.
Xie X, Cai X, Zhou F, et al. GPR37 promotes cancer growth by binding to CDK6 and represents a new theranostic target in lung adenocarcinoma. Pharmacol Res. 2022;183:106389.PubMed
65.
Wang M, Chen X, Fu G, Ge M. Glutathione peroxidase 2 overexpression promotes malignant progression and cisplatin resistance of KRAS-mutated lung cancer cells. Oncol Rep. 2022;48(6):1.
66.
An BC, Choi YD, Oh IJ, et al. GPx3-mediated redox signaling arrests the cell cycle and acts as a tumor suppressor in lung cancer cell lines. PLoS ONE. 2018;13(9):e0204170.PubMedPubMedCentral
Metadata
Title
Identification of molecular subgroups and establishment of risk model based on the response to oxidative stress to predict overall survival of patients with lung adenocarcinoma
Authors
Linzhuang Liu
Qinghua Hou
Baorong Chen
Xiyi Lai
Hanwen Wang
Haozhen Liu
Liusheng Wu
Sheng Liu
Kelin Luo
Jixian Liu
Publication date
01-12-2023
Publisher
BioMed Central
Published in
European Journal of Medical Research / Issue 1/2023
Electronic ISSN: 2047-783X
DOI
https://doi.org/10.1186/s40001-023-01290-5

Other articles of this Issue 1/2023

European Journal of Medical Research 1/2023 Go to the issue

Correspondence

Risk factors for clinical progression in patients with pulmonary Mycobacterium avium complex disease without culture-positive sputum: a single-center, retrospective study

Research

Predictors of cervical tumour size for outpatients with cervical cancer at the University of Gondar referral hospital: a retrospective study design

Review

Planning of physiotherapeutic procedure in patients after mandible reconstruction taking into account donor site: a literature review

Research

An in vivo study to investigate an original intramedullary bone graft harvesting technology

Research

Assessing vaginal wall indexes in premenopausal versus postmenopausal women by transrectal linear array high-frequency probe

Research

Drug metabolism-related gene ABCA1 augments temozolomide chemoresistance and immune infiltration abundance of M2 macrophages in glioma