Skip to main content
Top
Published in: Cancer Cell International 1/2024

Open Access 01-12-2024 | Research

Development and validation of a disulfidptosis and disulfide metabolism-related risk index for predicting prognosis in lung adenocarcinoma

Authors: Leqi Zhong, Wuguang Chang, Bin Luo, Wuyou Gao, Huanhuan He, Mouxiang Fang, Hongmu Li, Zhesheng Wen, Youfang Chen

Published in: Cancer Cell International | Issue 1/2024

Login to get access

Abstract

Background

Disulfidptosis is a recently proposed novel cell death mode in which cells with high SLC7A11 expression induce disulfide stress and cell death in response to glucose deficiency. The purpose of the research was to explore the function of disufidptosis and disulfide metabolism in the progression of lung adenocarcinoma (LUAD).

Methods

The RNA-seq data from TCGA were divided into high/low expression group on the base of the median expression of SLC7A11, and the characteristic of differentially expressed disulfide metabolism-related genes. Least absolute shrinkage and selection operator (LASSO) algorithm was conducted the disulfidptosis and disulfide metabolism risk index. The tumor mutation burden (TMB), mechanism, pathways, tumor microenvironment (TME), and immunotherapy response were assessed between different risk groups. The role of TXNRD1 in LUAD was investigated by cytological experiments.

Results

We established the risk index containing 5 genes. There are significant differences between different risk groups in terms of prognosis, TMB and tumor microenvironment. Additionally, the low-risk group demonstrated a higher rate of response immunotherapy in the prediction of immunotherapy response. Experimental validation suggested that the knockdown of TXNRD1 suppressed cell proliferation, migration, and invasion of LUAD.

Conclusion

Our research highlights the enormous potential of disulfidptosis and disulfide metabolism risk index in predicting the prognosis of LUAD. And TXNRD1 has great clinical translational ability.
Appendix
Available only for authorised users
Literature
1.
2.
go back to reference Hirsch FR, Scagliotti GV, Mulshine JL, Kwon R, Curran WJ Jr, Wu YL, Paz-Ares L. Lung cancer: current therapies and new targeted treatments. Lancet. 2017;389(10066):299–311.CrossRefPubMed Hirsch FR, Scagliotti GV, Mulshine JL, Kwon R, Curran WJ Jr, Wu YL, Paz-Ares L. Lung cancer: current therapies and new targeted treatments. Lancet. 2017;389(10066):299–311.CrossRefPubMed
4.
go back to reference Miller M, Hanna N. Advances in systemic therapy for non-small cell lung cancer. BMJ. 2021;375:n2363.CrossRefPubMed Miller M, Hanna N. Advances in systemic therapy for non-small cell lung cancer. BMJ. 2021;375:n2363.CrossRefPubMed
5.
go back to reference Minguet J, Smith KH, Bramlage P. Targeted therapies for treatment of non-small cell lung cancer—recent advances and future perspectives. Int J Cancer. 2016;138(11):2549–61.CrossRefPubMed Minguet J, Smith KH, Bramlage P. Targeted therapies for treatment of non-small cell lung cancer—recent advances and future perspectives. Int J Cancer. 2016;138(11):2549–61.CrossRefPubMed
6.
go back to reference Mamdani H, Matosevic S, Khalid AB, Durm G, Jalal SI. Immunotherapy in lung cancer: current landscape and future directions. Front Immunol. 2022;13:823618.CrossRefPubMedPubMedCentral Mamdani H, Matosevic S, Khalid AB, Durm G, Jalal SI. Immunotherapy in lung cancer: current landscape and future directions. Front Immunol. 2022;13:823618.CrossRefPubMedPubMedCentral
7.
go back to reference Goji T, Takahara K, Negishi M, Katoh H. Cystine uptake through the cystine/glutamate antiporter xCT triggers glioblastoma cell death under glucose deprivation. J Biol Chem. 2017;292(48):19721–32.CrossRefPubMedPubMedCentral Goji T, Takahara K, Negishi M, Katoh H. Cystine uptake through the cystine/glutamate antiporter xCT triggers glioblastoma cell death under glucose deprivation. J Biol Chem. 2017;292(48):19721–32.CrossRefPubMedPubMedCentral
8.
go back to reference Liu X, Nie L, Zhang Y, Yan Y, Wang C, Colic M, Olszewski K, Horbath A, Chen X, Lei G, et al. Actin cytoskeleton vulnerability to disulfide stress mediates disulfidptosis. Nat Cell Biol. 2023;25(3):404–14.CrossRefPubMedPubMedCentral Liu X, Nie L, Zhang Y, Yan Y, Wang C, Colic M, Olszewski K, Horbath A, Chen X, Lei G, et al. Actin cytoskeleton vulnerability to disulfide stress mediates disulfidptosis. Nat Cell Biol. 2023;25(3):404–14.CrossRefPubMedPubMedCentral
9.
go back to reference Rebhan M, Chalifa-Caspi V, Prilusky J, Lancet D. GeneCards: integrating information about genes, proteins and diseases. Trends Genet. 1997;13(4):163.CrossRefPubMed Rebhan M, Chalifa-Caspi V, Prilusky J, Lancet D. GeneCards: integrating information about genes, proteins and diseases. Trends Genet. 1997;13(4):163.CrossRefPubMed
10.
go back to reference Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, Smyth GK. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43(7):e47.CrossRefPubMedPubMedCentral Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, Smyth GK. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43(7):e47.CrossRefPubMedPubMedCentral
12.
go back to reference Mayakonda A, Lin DC, Assenov Y, Plass C, Koeffler HP. Maftools: efficient and comprehensive analysis of somatic variants in cancer. Genome Res. 2018;28(11):1747–56.CrossRefPubMedPubMedCentral Mayakonda A, Lin DC, Assenov Y, Plass C, Koeffler HP. Maftools: efficient and comprehensive analysis of somatic variants in cancer. Genome Res. 2018;28(11):1747–56.CrossRefPubMedPubMedCentral
13.
go back to reference Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102(43):15545–50.CrossRefPubMedPubMedCentral Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102(43):15545–50.CrossRefPubMedPubMedCentral
14.
go back to reference Barbie DA, Tamayo P, Boehm JS, Kim SY, Moody SE, Dunn IF, Schinzel AC, Sandy P, Meylan E, Scholl C, et al. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature. 2009;462(7269):108–12.CrossRefPubMedPubMedCentral Barbie DA, Tamayo P, Boehm JS, Kim SY, Moody SE, Dunn IF, Schinzel AC, Sandy P, Meylan E, Scholl C, et al. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature. 2009;462(7269):108–12.CrossRefPubMedPubMedCentral
15.
go back to reference Yoshihara K, Shahmoradgoli M, Martinez E, Vegesna R, Kim H, Torres-Garcia W, Trevino V, Shen H, Laird PW, Levine DA, et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun. 2013;4:2612.CrossRefPubMed Yoshihara K, Shahmoradgoli M, Martinez E, Vegesna R, Kim H, Torres-Garcia W, Trevino V, Shen H, Laird PW, Levine DA, et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun. 2013;4:2612.CrossRefPubMed
16.
go back to reference Tirosh I, Venteicher AS, Hebert C, Escalante LE, Patel AP, Yizhak K, Fisher JM, Rodman C, Mount C, Filbin MG, et al. Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma. Nature. 2016;539(7628):309–13.CrossRefPubMedPubMedCentral Tirosh I, Venteicher AS, Hebert C, Escalante LE, Patel AP, Yizhak K, Fisher JM, Rodman C, Mount C, Filbin MG, et al. Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma. Nature. 2016;539(7628):309–13.CrossRefPubMedPubMedCentral
17.
go back to reference Jiang P, Gu S, Pan D, Fu J, Sahu A, Hu X, Li Z, Traugh N, Bu X, Li B, et al. Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response. Nat Med. 2018;24(10):1550–8.CrossRefPubMedPubMedCentral Jiang P, Gu S, Pan D, Fu J, Sahu A, Hu X, Li Z, Traugh N, Bu X, Li B, et al. Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response. Nat Med. 2018;24(10):1550–8.CrossRefPubMedPubMedCentral
18.
go back to reference Braun DA, Hou Y, Bakouny Z, Ficial M, Sant’ Angelo M, Forman J, Ross-Macdonald P, Berger AC, Jegede OA, Elagina L, et al. Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma. Nat Med. 2020;26(6):909–18.CrossRefPubMedPubMedCentral Braun DA, Hou Y, Bakouny Z, Ficial M, Sant’ Angelo M, Forman J, Ross-Macdonald P, Berger AC, Jegede OA, Elagina L, et al. Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma. Nat Med. 2020;26(6):909–18.CrossRefPubMedPubMedCentral
19.
go back to reference Ren H, Zhang Z, Cheng X, Zou Z, Chen X, He C. Injectable, self-healing hydrogel adhesives with firm tissue adhesion and on-demand biodegradation for sutureless wound closure. Sci Adv. 2023;9(33):eadh4327.CrossRefPubMedPubMedCentral Ren H, Zhang Z, Cheng X, Zou Z, Chen X, He C. Injectable, self-healing hydrogel adhesives with firm tissue adhesion and on-demand biodegradation for sutureless wound closure. Sci Adv. 2023;9(33):eadh4327.CrossRefPubMedPubMedCentral
20.
go back to reference Zhou W, Lin Z, Xiong Y, Xue H, Song W, Yu T, Chen L, Hu Y, Panayi AC, Sun Y, et al. Dual-targeted nanoplatform regulating the bone immune microenvironment enhances fracture healing. ACS Appl Mater Interfaces. 2021;13(48):56944–60.CrossRefPubMed Zhou W, Lin Z, Xiong Y, Xue H, Song W, Yu T, Chen L, Hu Y, Panayi AC, Sun Y, et al. Dual-targeted nanoplatform regulating the bone immune microenvironment enhances fracture healing. ACS Appl Mater Interfaces. 2021;13(48):56944–60.CrossRefPubMed
21.
go back to reference Upadhyayula PS, Higgins DM, Mela A, Banu M, Dovas A, Zandkarimi F, Patel P, Mahajan A, Humala N, Nguyen TTT, et al. Dietary restriction of cysteine and methionine sensitizes gliomas to ferroptosis and induces alterations in energetic metabolism. Nat Commun. 2023;14(1):1187.CrossRefPubMedPubMedCentral Upadhyayula PS, Higgins DM, Mela A, Banu M, Dovas A, Zandkarimi F, Patel P, Mahajan A, Humala N, Nguyen TTT, et al. Dietary restriction of cysteine and methionine sensitizes gliomas to ferroptosis and induces alterations in energetic metabolism. Nat Commun. 2023;14(1):1187.CrossRefPubMedPubMedCentral
23.
24.
go back to reference Hanggi K, Ruffell B. Cell death, therapeutics, and the immune response in cancer. Trends Cancer. 2023;9(5):381–96.CrossRefPubMed Hanggi K, Ruffell B. Cell death, therapeutics, and the immune response in cancer. Trends Cancer. 2023;9(5):381–96.CrossRefPubMed
25.
go back to reference Hong M, Tao S, Zhang L, Diao LT, Huang X, Huang S, Xie SJ, Xiao ZD, Zhang H. RNA sequencing: new technologies and applications in cancer research. J Hematol Oncol. 2020;13(1):166.CrossRefPubMedPubMedCentral Hong M, Tao S, Zhang L, Diao LT, Huang X, Huang S, Xie SJ, Xiao ZD, Zhang H. RNA sequencing: new technologies and applications in cancer research. J Hematol Oncol. 2020;13(1):166.CrossRefPubMedPubMedCentral
26.
go back to reference Guo CR, Mao Y, Jiang F, Juan CX, Zhou GP, Li N. Computational detection of a genome instability-derived lncRNA signature for predicting the clinical outcome of lung adenocarcinoma. Cancer Med. 2022;11(3):864–79.CrossRefPubMed Guo CR, Mao Y, Jiang F, Juan CX, Zhou GP, Li N. Computational detection of a genome instability-derived lncRNA signature for predicting the clinical outcome of lung adenocarcinoma. Cancer Med. 2022;11(3):864–79.CrossRefPubMed
27.
go back to reference Zhang W, Qu H, Ma X, Li L, Wei Y, Wang Y, Zeng R, Nie Y, Zhang C, Yin K, et al. Identification of cuproptosis and immune-related gene prognostic signature in lung adenocarcinoma. Front Immunol. 2023;14:1179742.CrossRefPubMedPubMedCentral Zhang W, Qu H, Ma X, Li L, Wei Y, Wang Y, Zeng R, Nie Y, Zhang C, Yin K, et al. Identification of cuproptosis and immune-related gene prognostic signature in lung adenocarcinoma. Front Immunol. 2023;14:1179742.CrossRefPubMedPubMedCentral
28.
go back to reference Yue T, Li J, Zhu J, Zuo S, Wang X, Liu Y, Liu J, Liu X, Wang P, Chen S. Hydrogen sulfide creates a favorable immune microenvironment for colon cancer. Cancer Res. 2023;83(4):595–612.CrossRefPubMed Yue T, Li J, Zhu J, Zuo S, Wang X, Liu Y, Liu J, Liu X, Wang P, Chen S. Hydrogen sulfide creates a favorable immune microenvironment for colon cancer. Cancer Res. 2023;83(4):595–612.CrossRefPubMed
29.
go back to reference Wang M, Zhang G, Zhang Y, Cui X, Wang S, Gao S, Wang Y, Liu Y, Bae JH, Yang WH, et al. Fibrinogen alpha chain knockout promotes tumor growth and metastasis through integrin-AKT signaling pathway in lung cancer. Mol Cancer Res. 2020;18(7):943–54.CrossRefPubMed Wang M, Zhang G, Zhang Y, Cui X, Wang S, Gao S, Wang Y, Liu Y, Bae JH, Yang WH, et al. Fibrinogen alpha chain knockout promotes tumor growth and metastasis through integrin-AKT signaling pathway in lung cancer. Mol Cancer Res. 2020;18(7):943–54.CrossRefPubMed
30.
go back to reference Liu H, Yang Z, Zang L, Wang G, Zhou S, Jin G, Yang Z, Pan X. Downregulation of glutathione S-transferase A1 suppressed tumor growth and induced cell apoptosis in A549 cell line. Oncol Lett. 2018;16(1):467–74.PubMedPubMedCentral Liu H, Yang Z, Zang L, Wang G, Zhou S, Jin G, Yang Z, Pan X. Downregulation of glutathione S-transferase A1 suppressed tumor growth and induced cell apoptosis in A549 cell line. Oncol Lett. 2018;16(1):467–74.PubMedPubMedCentral
31.
go back to reference Labidi-Galy SI, Clauss A, Ng V, Duraisamy S, Elias KM, Piao HY, Bilal E, Davidowitz RA, Lu Y, Badalian-Very G, et al. Elafin drives poor outcome in high-grade serous ovarian cancers and basal-like breast tumors. Oncogene. 2015;34(3):373–83.CrossRefPubMed Labidi-Galy SI, Clauss A, Ng V, Duraisamy S, Elias KM, Piao HY, Bilal E, Davidowitz RA, Lu Y, Badalian-Very G, et al. Elafin drives poor outcome in high-grade serous ovarian cancers and basal-like breast tumors. Oncogene. 2015;34(3):373–83.CrossRefPubMed
32.
go back to reference Hunt KK, Wingate H, Yokota T, Liu Y, Mills GB, Zhang F, Fang B, Su CH, Zhang M, Yi M, et al. Elafin, an inhibitor of elastase, is a prognostic indicator in breast cancer. Breast Cancer Res. 2013;15(1):R3.CrossRefPubMedPubMedCentral Hunt KK, Wingate H, Yokota T, Liu Y, Mills GB, Zhang F, Fang B, Su CH, Zhang M, Yi M, et al. Elafin, an inhibitor of elastase, is a prognostic indicator in breast cancer. Breast Cancer Res. 2013;15(1):R3.CrossRefPubMedPubMedCentral
33.
go back to reference Lee HH, Wang YN, Yang WH, Xia W, Wei Y, Chan LC, Wang YH, Jiang Z, Xu S, Yao J, et al. Human ribonuclease 1 serves as a secretory ligand of ephrin A4 receptor and induces breast tumor initiation. Nat Commun. 2021;12(1):2788.CrossRefPubMedPubMedCentral Lee HH, Wang YN, Yang WH, Xia W, Wei Y, Chan LC, Wang YH, Jiang Z, Xu S, Yao J, et al. Human ribonuclease 1 serves as a secretory ligand of ephrin A4 receptor and induces breast tumor initiation. Nat Commun. 2021;12(1):2788.CrossRefPubMedPubMedCentral
34.
go back to reference Gencheva R, Arner ESJ. Thioredoxin reductase inhibition for cancer therapy. Annu Rev Pharmacol Toxicol. 2022;62:177–96.CrossRefPubMed Gencheva R, Arner ESJ. Thioredoxin reductase inhibition for cancer therapy. Annu Rev Pharmacol Toxicol. 2022;62:177–96.CrossRefPubMed
35.
go back to reference Shimada BK, Swanson S, Toh P, Seale LA. Metabolism of selenium, selenocysteine, and selenoproteins in ferroptosis in solid tumor cancers. Biomolecules. 2022;12(11):1581.CrossRefPubMedPubMedCentral Shimada BK, Swanson S, Toh P, Seale LA. Metabolism of selenium, selenocysteine, and selenoproteins in ferroptosis in solid tumor cancers. Biomolecules. 2022;12(11):1581.CrossRefPubMedPubMedCentral
36.
go back to reference Zhang J, Li X, Zhao Z, Cai W, Fang J. Thioredoxin signaling pathways in cancer. Antioxid Redox Signal. 2023;38(4–6):403–24.PubMed Zhang J, Li X, Zhao Z, Cai W, Fang J. Thioredoxin signaling pathways in cancer. Antioxid Redox Signal. 2023;38(4–6):403–24.PubMed
Metadata
Title
Development and validation of a disulfidptosis and disulfide metabolism-related risk index for predicting prognosis in lung adenocarcinoma
Authors
Leqi Zhong
Wuguang Chang
Bin Luo
Wuyou Gao
Huanhuan He
Mouxiang Fang
Hongmu Li
Zhesheng Wen
Youfang Chen
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2024
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-023-03204-1

Other articles of this Issue 1/2024

Cancer Cell International 1/2024 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine