High expression of six-transmembrane epithelial antigen of prostate 3 promotes the migration and invasion and predicts unfavorable prognosis in glioma

Recent studies have suggested that ferroptosis, a form of iron-dependent regulated cell death, might play essential roles in tumor initiation and progression. Six-transmembrane epithelial antigen of prostate 3 (STEAP3) is a ferrireductase involved in the regulation of intracellular iron homeostasis. However, the clinical significance and biological function of STEAP3 in human cancers remain poorly understood. Through a comprehensive bioinformatics analysis, we found that STEAP3 mRNA and protein expression were up-regulated in GBM, LUAD, and UCEC, and down-regulated in LIHC. Survival analysis indicated that STEAP3 had prognostic significance only in glioma. Multivariate Cox regression analysis revealed that high STEPA3 expression was correlated with poor prognosis. STEAP3 expression was significantly negatively correlated with promoter methylation level, and patients with lower STEAP3 methylation level had worse prognosis than those with higher STEAP3 methylation level. Single-cell functional state atlas showed that STEAP3 regulated epithelial-to-mesenchymal transition (EMT) in GBM. Furthermore, the results of wound healing and transwell invasion assays demonstrated that knocking down STEAP3 inhibited the migration and invasion of T98G and U251 cells. Functional enrichment analysis suggested that genes co-expressed with STEAP3 mainly participated in inflammation and immune-related pathways. Immunological analysis revealed that STEAP3 expression was significantly correlated with immune infiltration cells, including macrophages and neutrophils, especially the M2 macrophages. Individuals with low STEAP3 expression were more likely to respond to immunotherapy than those with high STEAP3 expression. These results suggest that STEAP3 promotes glioma progression and highlight its pivotal role in regulating immune microenvironment.