EPHA3, upregulated in high-risk histological subtypes of gastrointestinal stromal tumor, promotes GIST progression

Background To explore the expression pattern and functional role of EPH receptor A3 (EPHA3) in high-risk gastrointestinal stromal tumors (GISTs) and its potential relevance to tumor progression. Materials and methods Immunohistochemical (IHC) analysis was performed to evaluate EPHA3 expression across a pilot cohort of clinical GIST specimens with different risk stratifications. The biological functions of EPHA3 in vitro were assessed using (5-ethynyl-2’-deoxyuridine, EdU) assay, colony formation, apoptosis, wound-healing, and transwell assays in EPHA3-knockout GIST-430 cells. Furthermore, RNA sequencing (RNA-seq) analysis was utilized to identify differentially expressed genes and associated signaling pathways following EPHA3 knockout. Results EPHA3 expression was found to be elevated in high-risk GIST specimens compared with intermediate-risk cases. Loss-of-function assays demonstrated that EPHA3 knockout attenuated cell proliferation and migration while promoting apoptosis in vitro . Pathway enrichment analysis suggested that EPHA3 expression is associated with cell adhesion, extracellular matrix interaction, and mesenchymal-related phenotypic remodeling. Conclusions Our findings suggest that EPHA3 is upregulated in high-risk GIST and contributes to aggressive cellular behavior in vitro . These preliminary data indicate that EPHA3 may play a role in the malignant progression of GIST, although its clinical utility as a biomarker requires further validation in larger cohorts.