Background: Copper-induced cell death, or "cuproptosis," as an apoptotic process, has recently received much attention in human diseases. Recent studies on cuproptosis have provided novel insights into the pathogenesis of various diseases, especially cancers. However, the association between neuroblastoma (NB) and cuproptosis in terms of their clinical outcomes, tumorigenesis, and treatment response remains unclear.
Methods: To determine the role of cuproptosis in NB tumorigenesis and progression, this study employed a systematic technique to explore the characteristic patterns of 10 key cuproptosis-related genes (CUGs) in NB. Consensus clustering analysis of the TARGET and GEO databases divided the NB patients into two subgroups that showed different clinicopathological attributes, molecular patterns, survival outcomes, disease-associated pathways, tumor immune microenvironment (TIME) features, and treatment responses. Moreover, a cuproptosis scoring scheme was established, which divided the patients with NB into two groups with high scores and low scores as per the median score. Furthermore, this research developed a nomogram and risk signature on the basis of this cuproptosis score to better elucidate its function in predicting NB prognosis. In vitro experiments were carried out using Transwell Assay, HLECs tube formation assay, Colony formation assay, Western Blotting Assay, Immunohistochemical (IHC) Staining, Immunofluorescence (IF) Staining and Flow Cytometry Analysis.
Results: The results demonstrated that the established cuproptosis score and prediction model could effectively distinguish between the individuals in low and high-risk groups and had a high predictive value. Lastly, bioinformatics analysis and in vitro experiments enabled the identification of PDHA1, a key CUG, which was involved in both DNA replication-related pathways and the cell cycle. It was also associated with tumorigenesis and progression of NB.
Conclusion: Cuproptosis, especially PDHA1, play a crucial role in the TIME characteristics, tumor progression, and long-term prognosis of NB. The patterns of cuproptosis assessed in this research may improve the understanding of the overall concept of NB tumorigenesis, thus facilitating the development of more effective therapeutic interventions.
Keywords: Cell cycle; Cuproptosis; Neuroblastoma (NB); PDHA1; Tumor immune microenvironment (TIME).
© 2023. The Author(s).