Exploration of cuproptosis-Related Long Non-Coding RNA Signature to predict the clinical outcome and Immune Microenvironment in Cervical Cancer
Authors: Wang Bihui , Zhu Yuejie , Zhang Yulian , Ru Zhenyu , Ding Jianbing , Chen Zhifang 
Published: May 2023

BackgroundCervical cancer (CC) is the fourth most frequent cancer in women worldwide, Patients with CC, those at an advanced stage or with recurrent disease, have a poor prognosis with limited treatment options. Cuproptosis, which is regulated by mitochondrial ferredoxin 1-mediated protein lipoylation, is a newly discovered form of cell death. This study aimed to explore the potential prognostic value of cuproptosis-related lncRNAs and their relationship to immune microenvironment in cervical cancer.MethodsRNA-sequencing data and clinical data of female cervical cancer patients were obtained from The Cancer Genome Atlas (TCGA), and 19 cuproptosis-related genes were obtained from cuproptosis-related studies. 304 CC patients were randomly separated into training or validation cohorts in a 1:1 ratio. Pearson correlation analysis was used to screen out the lncrnas associated with copper-copper mineralization, and correlation analysis was conducted with 711 reported cuproptosis-related lncRNAs. Univariate, LASSO and multivariate Cox regression analyses were used to construct the characteristics of cuproptosis-related lncRNAs in the training cohort, and their prognostic value was further tested in the validation cohort. Patients were divided into high-and low-risk groups based on the median risk score. Independent prognostic analyses, ROC, C-index, and nomogram were carried out to assess the prognostic value of the signature. Subsequently, lncRNAs were analyzed for Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes Enrichment (KEGG), immune-related functions, and tumour mutation burden (TMB). Finally, we used tumor immune dysfunction and exclusion (TIDE) algorithms on immune escape and immunotherapy of cuproptosis-related lncRNAs for CC.ResultsA total of 10 cuproptosis-related lncRNAs were obtained, and patients were divided into high-and low-risk groups. We found that high-risk patients had worse overall survival (OS) and progression-free survival (PFS) and higher mortality. Independent prognostic analyses, ROC, C-index, and nomogram showed that the cuproptosis-related lncRNAs can accurately predict the prognosis of patients. The nomogram and heatmap showed a distinct distribution of the high- and low-risk cuproptosis-related lncRNAs. Enrichment analysis showed that the biological functions of lncRNAs are associated with tumor development. Tumor immune microenvironmental analyses the risk score was positively correlated with the number of M0 macrophages, and mast cell activated, negatively correlated with Dendritic cells resting, M1 macrophages, mast cell resting, T cell CD4 memory activated, T cell gamma delta and T cells CD8. we analyzed immune-related functions to evaluate the immune status of the low-risk and high-risk groups, and the results showed that HLA, cytolytic activity, inflammation-promoting, check point, T-cell co-inhibition, APC co-inhibition, APC co-stimulation, CCR, MHC-I, and type I IFN response were significantly more active in the low-risk group than in the high-risk group (p > 0.05). The results of the expression levels of immune checkpoint molecules in high-risk group and low-risk group showed that the expression levels of common immune checkpoint molecules such as PDCD1, CD274, HAVCR2, CTLA4, and TIGIT in low-risk group were all higher than those in high-risk group. In terms of TME scores, immune scores and ESTIMATE scores were higher in low-risk patients than in high-risk patients, with no difference in stromal scores between them, suggesting a higher infiltration of immune cells in the low-risk group. In addition, OS was poorer in patients with low TMB. We were surprised to find that there was a negative correlation between the TIDE and risk scores, further suggesting that high-risk patients might react more actively to immunotherapy.ConclusionWe identified a novel cuproptosis-related lncRNA signature which could precisely predict the prognosis of cervical cancer patients. Cuproptosis -related lncRNAs may may provide new insights into clinical applications and immunotherapy.