Pan-cancer analysis reveals copper transporters as promising potential targets

Background: Copper transport proteins (SLC31A1, ATP7A, ATP7B) regulate copper levels in the body and may be involved in tumor development. However, their comprehensive expression and function across various cancers remain unclear. Methods: The expressions of copper transporters in 33 tumors and normal tissues were analyzed using TCGA, GTEx, CCLE, ULCAN, and HPA databases. Cox regression assessed their impact on patient survival. Gene alterations were explored using cBioPortal. Spearman correlation tests were performed to investigate the associations between copper transporters and tumor mutation burden (TMB), microsatellite instability (MSI), and infiltration of immune cells. Gene functions were analyzed using STRING and GeneMANIA databases. Drug sensitivity was assessed using GSCALite database. ATP7B expression in lung squamous cell carcinoma (LUSC) was validated by immunohistochemical staining. Results: Copper transporters exhibited variable expression patterns across various cancer types, indicating their potential dual role as either oncogenes or tumor suppressor genes, depending on the cancer type. Significant associations were found between these transporters and tumor stage, as well as prognosis in most tumors studied. Pathway analysis identified links between copper transporters and tumor-related pathways like apoptosis and RAS/MAPK. Copy number variation (CNV) analysis revealed varying degrees of gene amplification and deletion of copper transporters in most tumors. Copper transporters exhibited strong correlations with immune features, including TMB, MSI, and immune-infiltrating cells, suggesting their potential role in guiding immunotherapy. They were also associated with sensitivity to various chemotherapeutic and immunotherapeutic drugs. Immunohistochemical tests validated the correlation between elevated ATP7B level and worse progression-free survival (PFS) in LUSC. Conclusion: Copper transporters may serve as potential tumor markers and therapeutic targets.