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Background: Cuproptosis is a novel form of cell death that is highly related to mitochondrial metabolism and mediated by protein lipoacetylation. This study systematically assessed the differential expression and genetic alterations of cuproptosis-related genes (CRGs) in head and neck squamous-cell carcinoma (HNSCC) and constructed CRG risk models to predict survival in patients with HNSCC. Methods: We investigated the expression of 19 CRGs in HNSCC and noncancerous tissues, and the relationship between mutation load, immune infiltration, and clinical features was examined based on data from public databases. CRG risk models were constructed by univariate Cox analysis and lasso regression and validated by independent datasets for their accuracy in predicting survival outcomes in patients with HNSCC. The expression distribution of CRGs in HNSCC cells was further explored in the HNSCC single-cell sequencing dataset. Results: NFE2L2, ATP7A, FDX1, LIAS, DLD, DLAT, PDHB, MTF1 and DBT were highly expressed in noncancerous samples, while GLS, CDKN2A and DLST were highly expressed in HNSCC samples (p < 0.05). Gene copy number variation frequency (CNV) revealed CDKN2A, FDX1 and DLAT copy number deletions and LIPT2 and NFE2L2 copy number increases. Ten CRGs were used to construct a risk model to predict overall survival (OS) in HNSCC, yielding reduced OS in the high-risk group compared to the low-risk group, training group (p = 9.733e − 05), and testing group (p = 0.040). The CRG risk model was significantly correlated with various immune cells, regulatory T cells (Tregs) and memory B cells were significantly negatively correlated (p = 0.027, p = 0.00084), and resting CD4 memory T cells was significantly positively correlated (p = 9e − 04). Most CRGs significantly affected the clinical characteristics of HNSCC. NFE2L2, SLC31A1, PDHA1, CDKN2A and DBT were highly expressed in epithelial cells of HNSCC, while SLC31A1, DBT and NFE2L2 were highly expressed in T cells, and SLC31A1 in B cells. In monocytes, NFE2L2, SLC31A1 and PDHA1 were highly expressed. Conclusion: The CRG risk model can be used as a potential prognostic factor for HNSCC patients and may provide new insights into cancer treatment from the perspective of copper metabolism. [ABSTRACT FROM AUTHOR]

Although the expression of tumor necrosis factor receptors (TNFRs) has been associated with clinicopathologic features of some other cancers, their roles in hypopharyngeal squamous cell carcinoma (HPSCC) have not been documented. Forty-five HPSCC specimens were analyzed for the expression of TNFR1 and TNFR2 and its relationship with clinicopathologic factors. Interaction between the two receptors and its effects on TNF-α was investigated by neutralizing TNFR1 and upregulation of TNFR2. The results indicated that, in HPSCC specimens, the expression of TNFR1 but not TNFR2 is associated with clinical staging, T stage, cervical lymph node metastasis, and histologic grade in HPSCC. In Fadu cells, when conjugating with its receptors, TNF-α mediates proliferation effects, and neutralizing TNFR1 and/or upregulating TNFR2 evokes proliferation-inhibiting and apoptosis-inducing effects and potentiates cisplatin (DDP)-induced growth inhibition and apoptosis induction. In conclusion, interaction of TNFR1 with TNFR2 determines the biological characters of HPSCC, and TNFR1 may dominate this process. Moreover, interaction between the two receptors plays important roles in determining the fates of HPSCC cells and thus may serve as a therapeutic target for developing new therapeutic strategies for HPSCC. [ABSTRACT FROM AUTHOR]