Abstract
BACKGROUND: Tumors characterized by high cellular stemness often have unfavorable clinical outcomes, primarily due to their heightened potential for metastasis and resistance to chemotherapy. Among the model genes, the clinical relevance and prognostic significance of Niemann-Pick type C2 (NPC2) in gastric cancer (GC) remained largely unexplored. AIM: To identify stemness-associated genes in GC. METHODS: In this study, epithelial cells were categorized as either tumor or normal epithelial cells using the infer copy number variation method. Stemness scores were calculated for both cell types. The hierarchical Weighted Gene Co-expression Network Analysis identified two gene modules with the strongest association with stemness. Prognostically significant stemness-related genes were pinpointed using univariate Cox regression based on The Cancer Genome Atlas dataset. A predictive model related to stemness was constructed using Least Absolute Shrinkage and Selection Operator regression followed by multivariate Cox analysis. RESULTS: Functional roles of NPC2 were validated using single-cell and bulk RNA sequencing data. Further experimental validation revealed that elevated NPC2 expression promoted tumor cell stemness, invasiveness, migratory ability, and resistance to standard chemotherapeutic agents. Importantly, high NPC2 expression correlated with poorer overall survival in GC patients. CONCLUSION: In summary, the proposed model offers prognostic insights that outperform traditional clinical staging and may inform more tailored therapeutic approaches for gastric cancer management.