Screening of PDSS1 as a potential biomarker for hepatocellular carcinoma based on a copper-related prognostic signature through bulk and single-cell RNA-sequencing analysis

Background: Currently, there is few literature comprehensively analyzing landscape of cuproptosis-related genes (CRGs) in liver hepatocellular carcinoma (LIHC) with multiple omics approaches. Aims: Using comprehensive analysis, we aim to find out how CRGs works on LIHC. Method: With data from The Cancer Genome Atlas (TCGA) database, we constructed a prognostic prediction model for CGRs using LASSO regression analysis and performed immune infiltration analysis using the same dataset. To validate findings, we utilized RNA expression data from the International Cancer Genome Consortium (ICGC). Furthermore, we analyzed the enrichment and features of CRGs in epithelial cells using single-cell RNA sequencing (scRNA-seq) data. To validate the reliability of findings, we performed several experiments including RT-PCR, cloning formation assay, scratch assay, and Transwell assay. Result: We have constructed a high-precision risk scoring model composed of CRGs for predicting prognosis in TCGA-LIHC. Reliability of the risk prognosis model was confirmed through Kaplan-Meier curve analysis, time-dependent ROC analysis, and multivariate regression analysis. Furthermore, we found knocking down PDSS1 increased sensitivity of LIHC cells to copper ions, and both proliferation and migration abilities were significantly reduced. Finally, we comprehensively characterized the features of CRGs in LIHC through scRNA-seq. Conclusion: Current research predicts cuproptosis may be involved in the pathogenesis of LIHC and associated with patient prognosis. Tumor cells with high cuproptosis features are closely related to tumor-associated macrophages (TAMs), which leads to the activation of tumor-related transcription factors (TFs) and a high metabolic microenvironment. Identified CRGs can serve as candidate biomarkers or therapeutic targets for LIHC.