GNA15 as a potential prognostic and immunological biomarker in ccRCC based on bioinformatics analysis and experimental verification.

As the most common and aggressive subtype of renal cancer, clear cell renal cell carcinoma (ccRCC) often shows poor responsiveness to current therapeutic strategies. Although GNA15, a G protein alpha subunit, has been associated with the progression of multiple tumor types, its functional significance in ccRCC remains largely undefined. Public datasets were used to profile GNA15 expression across cancers, and its links to prognosis, genomic diversity, stemness, and immune infiltration were analyzed with multiple computational tools. In ccRCC, transcriptomic and protein expression levels were validated using immunofluorescence and western blotting. Functional assays, including colony formation, transwell migration, tumor spheroid formation, and GSEA, were used to investigate the biological role of GNA15. The effects of GNA15 knockdown were assessed in renal cancer cell lines. GNA15 was aberrantly upregulated in multiple cancers and significantly elevated in ccRCC tissues and cell lines. High GNA15 expression correlated with poor overall survival and advanced clinical stage. It was also positively associated with tumor heterogeneity, stemness, and immunosuppressive microenvironment characteristics, particularly M2 macrophage and neutrophil infiltration. GSEA identified enrichment in oncogenic pathways, including JAK-STAT, Wnt, and Notch signaling. In vitro knockdown of GNA15 reduced tumor cell proliferation, migration, spheroid formation, and expression of stemness markers and PD-L1. Our results highlight GNA15 as a novel oncogenic and immune-related contributor to ccRCC progression, supporting its potential as a prognostic biomarker and therapeutic target.