Identification and validation of a novel cuproptosis-related signature as a prognostic model for lung adenocarcinoma

Yuqiao Chen; Lu Tang; Wentao Huang; Youyu Zhang; Fakolade Hannah Abisola; Linfeng Li

doi:10.3389/fendo.2022.963220

Identification and validation of a novel cuproptosis-related signature as a prognostic model for lung adenocarcinoma

Front Endocrinol (Lausanne). 2022 Oct 24:13:963220. doi: 10.3389/fendo.2022.963220. eCollection 2022.

Authors

Yuqiao Chen¹, Lu Tang², Wentao Huang¹, Youyu Zhang¹, Fakolade Hannah Abisola¹, Linfeng Li^{1

3

4}

Affiliations

¹ Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.
² Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
³ National Clinical Research Center for Geriatric Disorders, Changsha, Hunan, China.
⁴ Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, Hunan, China.

Abstract

Background: Cuproptosis is a novel form of copper-induced cell death that targets lipoylated tricarboxylic acid (TCA) cycle proteins. However, its prognostic role in lung adenocarcinoma (LUAD) remains unclear. This study aimed to establish a cuproptosis-related prognostic signature for patients with LUAD.

Methods: Transcriptome data of LUAD samples were extracted from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The prognostic value of cuproptosis-related genes (CRGs) was investigated using Cox regression analysis to develop a cuproptosis-related prognostic model. Kyoto Encyclopedia of Genes and Genomes (KEGG), gene ontology (GO) and gene set variation analysis (GSVA) were conducted to characterize different biological activities or pathways between high- or low-CRG groups. The expression pattern and prognostic values of CRGs were validated in 37 paired tumor-normal samples using quantitative PCR. Furthermore, in vitro experiments were performed to investigate the relationship between cuproptosis and CRG expression and to explore the function of target genes in cuproptosis.

Results: Among the 36 CRGs, 17 genes were upregulated, and 3 genes were downregulated in LUAD. A total of 385 CRGs were identified using Pearson correlation analysis. A cuproptosis-related signature was constructed using least absolute shrinkage and selection operator (LASSO) analysis. The prognostic value of the cuproptosis-related signature was validated in six external validation cohorts and in LUAD specimens from our facility. Patients in the high-risk group based on the CRG signature score had shorter overall survival than those in the low-risk group in both the datasets and clinical specimens. In vitro experiments revealed that the expression of BARX1, GFRA3, and KHDRBS2 was upregulated after cuproptosis was induced by elesclomol-CuCL₂, whereas the upregulation was suppressed on pretreatment with tetrathiomolybdate (TTM), a chelator of copper. Further, the cell proliferation assay revealed that the BARX1 and GFRA3 deficiency facilities the cuproptosis induced by elesclomol-CuCL₂.

Conclusion: This study established a new CRG signature that can be used to predict the OS of LUAD patients. Moreover, the knockdown of BARX1 and GFRA3 could increase the sensitivity of LUAD cells to the cuproptosis.

Keywords: bioinformatic analysis; cuproptosis; lung cancer; overall survival; prognostic signature.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma of Lung* / genetics
Adenocarcinoma of Lung* / metabolism
Adenocarcinoma of Lung* / pathology
Apoptosis*
Copper
Gene Expression Regulation, Neoplastic
Humans
Lung Neoplasms* / genetics
Lung Neoplasms* / pathology
Prognosis

Substances

Copper
elesclomol