ATP7A as a prognostic biomarker and potential therapeutic target in gastric cancer.

Objectives: To investigate the roles of Cu transporter ATPase copper transporting alpha (ATP7A) in gastric cancer (GC) progression and prognosis.

Methods: ATP7A expression was investigated using databases, immunohistochemistry (IHC) and qPCR in tumor tissues and GC cell lines. Diagnostic and prognostic value of ATP7A was assessed by Receiver Operating Characteristic (ROC) and Kaplan-Meier curve, respectively. The roles of ATP7A were explored using protein-protein interaction (PPI), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA), ssGSEA algorithm and Tumor Immune Estimation Resource (TIMER) databases. Subsequently, the effects of ATP7A were evaluated by Cell Counting Kit-8 (CCK-8), colony formation, and transwell assays.

Results: ATP7A overexpression was associated with a higher IHC score and a larger area under the ROC curve (0.746). Elevated ATP7A expression correlated with shorter survival time, greater invasion depth of GC lesions, advanced pathological stages, and older age in GC patients. Comprehensive analysis revealed that ATP7A was involved in copper ion transport, transition metal ion homeostasis, cellular transition metal ion homeostasis, and copper ion homeostasis. Additionally, ATP7A was linked to key signaling pathways, including Hedgehog, Wnt/β-catenin, and Notch, along with the top 10 hub genes. Furthermore, ATP7A played a role in immune infiltration, influencing T cells, dendritic cells, B cells, macrophages, and neutrophils, as well as the expression of immune checkpoints such as Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA-4), Programmed Cell Death Protein 1 Ligand 1 (PD-L1), T-Cell Immunoglobulin, and Mucin Domain-Containing Protein 3 (TIM-3). Experimental validation demonstrated that silencing ATP7A suppressed GC cell proliferation, colony formation, migration, and invasion.

Conclusion: ATP7A promoted GC progression and acted as a promising prognostic target for the treatment of GC.