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Construction and validation of a novel ferroptosis-related prognostic signature for lung adenocarcinoma

BACKGROUND: Lung cancer has the highest prevalence and mortality of all cancers, and lung adenocarcinoma (LUAD) occupies the largest proportion of lung cancers. Herein, this study is aimed at constructing a ferroptosis-related prognostic signature for LUAD and conducting functional analysis based on...

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Autores principales: Yang, Li, Fan, Xinxin, Zhou, Chao, Wang, Ziqi, Cui, Zelong, Wu, Xuan, Xu, Zhiwei, Yang, Jia, Zhang, Xiaoju
Formato: Online Artículo Texto
Lenguaje:English
Publicado: AME Publishing Company 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10483076/
https://www.ncbi.nlm.nih.gov/pubmed/37691861
http://dx.doi.org/10.21037/tlcr-23-351
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author Yang, Li
Fan, Xinxin
Zhou, Chao
Wang, Ziqi
Cui, Zelong
Wu, Xuan
Xu, Zhiwei
Yang, Jia
Zhang, Xiaoju
author_facet Yang, Li
Fan, Xinxin
Zhou, Chao
Wang, Ziqi
Cui, Zelong
Wu, Xuan
Xu, Zhiwei
Yang, Jia
Zhang, Xiaoju
author_sort Yang, Li
collection PubMed
description BACKGROUND: Lung cancer has the highest prevalence and mortality of all cancers, and lung adenocarcinoma (LUAD) occupies the largest proportion of lung cancers. Herein, this study is aimed at constructing a ferroptosis-related prognostic signature for LUAD and conducting functional analysis based on the signature, highlighting the importance of ferroptosis in LUAD. METHODS: We employed RNA-sequencing (RNA-seq) and clinical data from The Cancer Genome Atlas (TCGA) database. Univariate Cox regression, Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis were conducted to build the ferroptosis-related genes (FRGs) prognostic signature. The efficacy of this FRG signature was further analyzed with Kaplan-Meier (KM) plot, multivariate Cox regression, and the receiver operating characteristic (ROC) curves. Enrichment analysis was used to evaluate key pathways. The expression of immunomodulators, immune infiltration status, and drug sensitivity correlation were explored to predict the response to various therapies. The expression of FRGs was validated in LUAD samples with western blot (WB) and immunohistochemistry (IHC) staining. Cell viability assay and lipid peroxidation detection were measured after small interfering RNA (siRNA) knockdown of two FRGs in lung cancer cell lines. RESULTS: A seven-gene signature was constructed and used to divide LUAD patients into high- and low-risk groups. High-risk patients were notably related to shorter overall survival (OS), and multivariate Cox regression demonstrated that our signature was an independent predictor of OS. ROC curve analysis presented a maximum area under the curve (AUC) value of 0.740 for the experimental cohort and 0.705 for the validation cohort. The low-risk group showed higher levels of plasma cell infiltration and higher expression of programmed cell death protein 1 (PDCD1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4). Ferroptosis inducers such as talazoparib or cisplatin had lower IC50 values in the high-risk group, while navitoclax (BCL-2 gene family inhibition and apoptosis inducer) had higher IC50 values in the high-risk group. Additionally, peroxiredoxin-6 (PRDX6) and acyl-CoA synthetase long chain family member 3 (ACSL3) were upregulated in LUAD tissues. Lipid peroxide assay showed that silencing PRDX6 or ACSL3 promoted lipid peroxidation and ferroptosis in lung cancer cells. CONCLUSIONS: Our novel ferroptosis-related signature shows potential clinical and functional importance in LUAD patients, and further research on ferroptosis as a therapeutic target in LUAD is warranted.
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spelling pubmed-104830762023-09-08 Construction and validation of a novel ferroptosis-related prognostic signature for lung adenocarcinoma Yang, Li Fan, Xinxin Zhou, Chao Wang, Ziqi Cui, Zelong Wu, Xuan Xu, Zhiwei Yang, Jia Zhang, Xiaoju Transl Lung Cancer Res Original Article BACKGROUND: Lung cancer has the highest prevalence and mortality of all cancers, and lung adenocarcinoma (LUAD) occupies the largest proportion of lung cancers. Herein, this study is aimed at constructing a ferroptosis-related prognostic signature for LUAD and conducting functional analysis based on the signature, highlighting the importance of ferroptosis in LUAD. METHODS: We employed RNA-sequencing (RNA-seq) and clinical data from The Cancer Genome Atlas (TCGA) database. Univariate Cox regression, Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis were conducted to build the ferroptosis-related genes (FRGs) prognostic signature. The efficacy of this FRG signature was further analyzed with Kaplan-Meier (KM) plot, multivariate Cox regression, and the receiver operating characteristic (ROC) curves. Enrichment analysis was used to evaluate key pathways. The expression of immunomodulators, immune infiltration status, and drug sensitivity correlation were explored to predict the response to various therapies. The expression of FRGs was validated in LUAD samples with western blot (WB) and immunohistochemistry (IHC) staining. Cell viability assay and lipid peroxidation detection were measured after small interfering RNA (siRNA) knockdown of two FRGs in lung cancer cell lines. RESULTS: A seven-gene signature was constructed and used to divide LUAD patients into high- and low-risk groups. High-risk patients were notably related to shorter overall survival (OS), and multivariate Cox regression demonstrated that our signature was an independent predictor of OS. ROC curve analysis presented a maximum area under the curve (AUC) value of 0.740 for the experimental cohort and 0.705 for the validation cohort. The low-risk group showed higher levels of plasma cell infiltration and higher expression of programmed cell death protein 1 (PDCD1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4). Ferroptosis inducers such as talazoparib or cisplatin had lower IC50 values in the high-risk group, while navitoclax (BCL-2 gene family inhibition and apoptosis inducer) had higher IC50 values in the high-risk group. Additionally, peroxiredoxin-6 (PRDX6) and acyl-CoA synthetase long chain family member 3 (ACSL3) were upregulated in LUAD tissues. Lipid peroxide assay showed that silencing PRDX6 or ACSL3 promoted lipid peroxidation and ferroptosis in lung cancer cells. CONCLUSIONS: Our novel ferroptosis-related signature shows potential clinical and functional importance in LUAD patients, and further research on ferroptosis as a therapeutic target in LUAD is warranted. AME Publishing Company 2023-08-28 2023-08-30 /pmc/articles/PMC10483076/ /pubmed/37691861 http://dx.doi.org/10.21037/tlcr-23-351 Text en 2023 Translational Lung Cancer Research. All rights reserved. https://creativecommons.org/licenses/by-nc-nd/4.0/Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Original Article
Yang, Li
Fan, Xinxin
Zhou, Chao
Wang, Ziqi
Cui, Zelong
Wu, Xuan
Xu, Zhiwei
Yang, Jia
Zhang, Xiaoju
Construction and validation of a novel ferroptosis-related prognostic signature for lung adenocarcinoma
title Construction and validation of a novel ferroptosis-related prognostic signature for lung adenocarcinoma
title_full Construction and validation of a novel ferroptosis-related prognostic signature for lung adenocarcinoma
title_fullStr Construction and validation of a novel ferroptosis-related prognostic signature for lung adenocarcinoma
title_full_unstemmed Construction and validation of a novel ferroptosis-related prognostic signature for lung adenocarcinoma
title_short Construction and validation of a novel ferroptosis-related prognostic signature for lung adenocarcinoma
title_sort construction and validation of a novel ferroptosis-related prognostic signature for lung adenocarcinoma
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10483076/
https://www.ncbi.nlm.nih.gov/pubmed/37691861
http://dx.doi.org/10.21037/tlcr-23-351
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