Development and validation of a novel 5 cuproptosis-related long noncoding RNA signature to predict diagnosis, prognosis, and drug therapy in clear cell renal cell carcinoma.

Abstract

Cuproptosis has been reported as a new form of cell death. However, its potential mechanism of action in clear cell renal cell carcinoma (ccRCC) remains unclear. Therefore, we systematically clarified the role of cuproptosis in ccRCC and aimed to develop a novel signature of cuproptosis-related long noncoding RNAs (lncRNA) (CRLs) to assess the clinical characteristics of ccRCC patients. Gene expression, copy number variation, gene mutation, and clinical data for ccRCC were obtained from The Cancer Genome Atlas (TCGA). CRL signature was constructed with least absolute shrinkage and selection operator (LASSO) regression analysis. The clinical diagnostic value of the signature was verified by clinical data. The prognostic value of the signature was detected by Kaplan-Meier analysis and receiver operating characteristic (ROC) curve. The prognostic value of the nomogram was evaluated by calibration curves, ROC curves, and decision curve analysis (DCA). Gene set enrichment analysis (GSEA), single sample GSEA (ssGSEA) and cell type identification by estimating relative subsets of RNA transcripts (CIBERSORT) algorithm were used to analyze the differences of immune function and immune cell infiltration among different risk groups. Prediction of clinical treatment differences in populations with different risks and susceptibilities was completed with R package (The R Foundation of Statistical Computing). Verification of key lncRNA expression was performed by quantitative real-time polymerase chain reaction (qRT-PCR). The cuproptosis-related genes were extensively dysregulated in ccRCC. A total of 153 differentially expressed prognostic CRLs were identified in ccRCC. Furthermore, a 5-lncRNA signature (AC015912.3, AC026401.3, AC103706.1, AC134312.5, and EMX2OS) were obtained that showed good performance in the diagnosis and prognosis of ccRCC. The nomogram could more accurately predict overall survival (OS). Immune functions such as T-cell and B-cell receptor signaling pathways showed differences between different risk groups. Clinical treatment value analysis showed that the signature may be able to effectively guide immunotherapy and target therapy. In addition, qRT-PCR results showed significant differences in the expression of key lncRNAs in ccRCC. Cuproptosis plays an important role in the progression of ccRCC. The 5-CRL signature can guide the prediction of clinical characteristics and tumor immune microenvironment of ccRCC patients.