The Role of STEAP3 in Pathogenesis of Gliomas: An Independent Prognostic Factor and Regulator of Ferroptosis.

Objective: Gliomas are common intracranial tumors with high malignancy and poor prognosis, classified into glioblastomas (GBM) and low-grade glioma (LGG). However, the regulatory mechanisms of glioma tumorigenesis remain unclear. This study aimed to investigate the role of six-transmembrane epithelial antigen of the prostate 3 (STEAP3) in glioma prognosis and explore its potential as a therapeutic target, as well as the ferroptosis-related molecular mechanism in progression of gliomas.

Methods: Cox regression analyses were used to identify prognostic factors of gliomas patients from Cancer Genome Atlas (TCGA) database and DESeq2 package was used for differential gene expression comparisons between Grade 2 and Grade 4 gliomas. Wilcoxon rank-sum test was used to compare the STEAP3 expression levels between glioma tissues and normal controls in Xiantao platform, as well as between TCGA glioma samples and GTEx normal samples. A protein-protein interaction (PPI) network was constructed using STRING database information, with hub genes identified through Cytoscape software. Cell viability was determined by MTT assay. Cell proliferation was determined by BrdU incorporation and clone formation assay. GSH and MDA concentration was determined according to kit protocols. The expression of STEAP3, Nrf2, GPX4 was determined by western blotting analysis.

Results: Our results revealed that STEAP3 is overexpressed in glioma tissues compared to normal counterparts and correlates with poor overall survival (OS). High STEAP3 expression significantly correlates with various clinical-pathological features such as age, histological type, treatment response, World Health Organization (WHO) grade, isocitrate dehydrogenase (IDH) status, and survival events. Knockdown STEAP3 inhibited cell proliferation and enhanced erastin-induced ferroptosis in U87 and U138 cells. Moreover, knockdown STEAP3 in glioma cells decreased the GSH levels and increased the production of MDA probably by inhibiting the Nrf2/GPX4 related signaling pathway.

Conclusion: STEAP3 serves as an independent biomarker for glioma prognosis with significant diagnostic value. High STEAP3 expression was correlated with poor overall outcomes of glioma patients. Knockdown of STEAP3 significantly suppressed the proliferation of glioma cells and increased erastin-induced ferroptosis via Nrf2/GPX4 pathway.