A novel cuproptosis-related subtypes and gene signature associates with immunophenotype and predicts prognosis accurately in neuroblastoma

Abstract

BackgroundNeuroblastoma (NB) is the most frequent solid tumor in pediatrics, which accounts for roughly 15% of cancer-related mortality in children. NB exhibited genetic, morphologic, and clinical heterogeneity, which limited the efficacy of available therapeutic approaches. Recently, a new term ‘cuproptosis’ has been used to denote a unique biological process triggered by the action of copper. In this instance, selectively inducing copper death is likely to successfully overcome the limitations of conventional anticancer drugs. However, there is still a gap regarding the role of cuproptosis in cancer, especially in pediatric neuroblastoma.MethodsWe characterized the specific expression of cuproptosis-related genes (CRGs) in NB samples based on publicly available mRNA expression profile data. Consensus clustering and Lasso-Cox regression analysis were applied for CRGs in three independent cohorts. ESTIMATE and Xcell algorithm was utilized to visualize TME score and immune cell subpopulations’ relative abundances. Tumor Immune Dysfunction and Exclusion (TIDE) score was used to predict tumor response to immune checkpoint inhibitors. To decipher the underlying mechanism, GSVA was applied to explore enriched pathways associated with cuproptosis signature and Connectivity map (CMap) analysis for drug exploration. Finally, qPCR verified the expression levels of risk-genes in NB cell lines. In addition, PDHA1 was screened and further validated by immunofluorescence in human clinical samples and loss-of-function assays.ResultsWe initially classified NB patients according to CRGs and identified two cuproptosis-related subtypes that were associated with prognosis and immunophenotype. After this, a cuproptosis-related prognostic model was constructed and validated by LASSO regression in three independent cohorts. This model can accurately predict prognosis, immune infiltration, and immunotherapy responses. These genes also showed differential expression in various characteristic groups of all three datasets and NB cell lines. Loss-of-function experiments indicated that PDHA1 silencing significantly suppressed the proliferation, migration, and invasion, in turn, promoted cell cycle arrest at the S phase and apoptosis of NB cells.ConclusionsTaken together, this study may shed light on new research areas for NB patients from the cuproptosis perspective.

Optimal combination of MYCN differential gene and cellular senescence gene predicts adverse outcomes in patients with neuroblastoma

“…NB is the most common extracranial tumor in children, and there is currently no standardized prognostic evaluation system, which due to NB is a highly heterogeneous tumor ( 5 , 10 ). Despite the utilization of genetic testing techniques in clinical practice, only a limited number of genes have established prognostic value in NB ( 24 , 25 ). It is still unclear why some patients experience poor clinical outcomes despite the absence of commonly detected high-risk genes, while others exhibit positive clinical outcomes despite the presence of individual high-risk gene expression.…”

“…*p < 0.1; **p < 0.05; ***p < 0.01; ****p < 0.001, respectively. limited number of genes have established prognostic value in NB (24,25). It is still unclear why some patients experience poor clinical outcomes despite the absence of commonly detected high-risk genes, while others exhibit positive clinical outcomes despite the presence of individual high-risk gene expression.…”

Comparison of Deeply Versus Mildly Invasive Mesothelioma Proteomes Identifies Potential Links Between Mitochondrial Acadvl Expression and Biomarkers of Aggressiveness

“…A second study by Olou et al pointed to its involvement in adipocyte maintenance and secretion of the cancer-promoting cytokine IL-6 [27]. Finally, Tian et al showed that silencing this gene suppressed proliferation, migration, and invasion in neuroblastoma [28]. Within mitochondrial proteins exhibiting a decrease, the two enzymes of the TCA cycle, succinate dehydrogenase (encoded by Sdha) and fumarate hydratase (encoded by Fh), which represent potential tumor suppressors, were frequently reported to be downregulated in cancers [29,30].…”