ETV1 Promotes Glioma Progression via miR-3175/STEAP2 Axis

Glioblastoma is lethal brain tumor with dismal prognosis. ETV1, an ETS family transcription factor, has been implicated in multiple malignancies, yet its precise role and regulatory mechanisms in glioma progression remain incompletely defined. This study investigated the role of ETV1 in maintaining the malignant phenotype of high-grade gliomas through a novel regulatory axis involving microRNA-3175 (miR-3175) and STEAP2. ETV1 expression was analyzed in TCGA glioma datasets (n = 692) and 85 patient tissue specimens using bioinformatics, quantitative RT-PCR, Western blotting, and immunohistochemistry. ETV1 function was assessed through gain-of-function and loss-of-function studies in glioma cell lines (U251, A172) and validated in nude mouse xenografts with bioluminescence imaging. The ETV1-miR-3175-STEAP2 regulatory axis was characterized using chromatin immunoprecipitation, luciferase reporter assays, biotin-streptavidin pulldown, RNA immunoprecipitation, and rescue experiments. ETV1 was significantly upregulated in gliomas, with expression correlating to tumor grade and reduced overall patient survival. ETV1 overexpression promoted glioma cell proliferation, migration, and invasion in vitro and enhanced tumor growth while reducing survival in vivo, with elevated bioluminescence radiance indicating enhanced tumorigenicity, whereas ETV1 knockdown produced opposite effects and diminished bioluminescent signals. ETV1 transcriptionally activated miR-3175 through direct binding to its promoter. miR-3175 directly targeted and suppressed STEAP2 expression via conserved 3'UTR binding sites. STEAP2 functioned as a tumor suppressor; overexpression inhibited malignant phenotypes. Rescue experiments confirmed miR-3175 and STEAP2 mediate ETV1-driven glioma progression through a functional ETV1/miR-3175/STEAP2 regulatory axis. This study revealed a novel ETV1/miR-3175/STEAP2 regulatory axis driving glioma tumorigenesis and identified potential therapeutic targets for intervention.