Identification and Validation of a Novel Cuproptosis-related Signature As a Prognostic Model for Lung Adenocarcinoma

Overview

Journal Front Endocrinol (Lausanne)

Specialty Endocrinology

Date 2022 Nov 10

PMID 36353226

Authors

Yuqiao Chen

Lu Tang

Wentao Huang

Youyu Zhang

Fakolade Hannah Abisola

Linfeng Li

Affiliations

Soon will be listed here.

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, 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. experiments revealed that the expression of , , and was upregulated after cuproptosis was induced by elesclomol-CuCL, whereas the upregulation was suppressed on pretreatment with tetrathiomolybdate (TTM), a chelator of copper. Further, the cell proliferation assay revealed that the and deficiency facilities the cuproptosis induced by elesclomol-CuCL.

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

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