AUTHOR=Chen Yuqiao , Tang Lu , Huang Wentao , Zhang Youyu , Abisola Fakolade Hannah , Li Linfeng 

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

JOURNAL=Frontiers in Endocrinology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.963220

DOI=10.3389/fendo.2022.963220

ISSN=1664-2392

ABSTRACT=<sec><title>Background</title><p>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.</p></sec><sec><title>Methods</title><p>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, <italic>in vitro</italic> experiments were performed to investigate the relationship between cuproptosis and CRG expression and to explore the function of target genes in cuproptosis.</p></sec><sec><title>Results</title><p>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. <italic>In vitro</italic> experiments revealed that the expression of <italic>BARX1</italic>, <italic>GFRA3</italic>, and <italic>KHDRBS2</italic> was upregulated after cuproptosis was induced by elesclomol–CuCL<sub>2</sub>, whereas the upregulation was suppressed on pretreatment with tetrathiomolybdate (TTM), a chelator of copper. Further, the cell proliferation assay revealed that the <italic>BARX1</italic> and <italic>GFRA3</italic> deficiency facilities the cuproptosis induced by elesclomol–CuCL<sub>2</sub>.</p></sec><sec><title>Conclusion</title><p>This study established a new CRG signature that can be used to predict the OS of LUAD patients. Moreover, the knockdown of <italic>BARX1</italic> and <italic>GFRA3</italic> could increase the sensitivity of LUAD cells to the cuproptosis.</p></sec>