BACKGROUND: Plexins (PLXNs) are cell surface receptors for class 3 semaphorins and play critical roles in immune regulation and tumorigenesis. Plexin A3 (PLXNA3) is involved primarily in nervous system development, but its function in colorectal cancer (CRC) remains poorly understood. Recent computational studies have identified PLXNA3 as a potential prognostic biomarker in CRC, yet experimental validation of its biological role is lacking. METHODS: PLXNA3 expression and its prognostic significance were analyzed using data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Immune infiltration correlations were assessed via TIMER2.0. Gene set enrichment analysis (GSEA) was performed to predict potential biological functions. For experimental validation, qRT‒PCR was used to assess PLXNA3 expression in CRC cell lines, and CCK-8, colony formation, and Transwell assays were conducted to evaluate the effects of PLXNA3 knockdown on cell proliferation and migration. RESULTS: PLXNA3 expression was significantly upregulated in CRC tissues and associated with poor overall survival in both the TCGA and GEO cohorts. High PLXNA3 expression correlated with advanced tumor stage and metastasis. PLXNA3 expression was positively correlated with the infiltration levels of CD4 + T cells, macrophages, neutrophils, and dendritic cells. Functional enrichment analysis suggested potential involvement in glucose metabolism and axonal guidance pathways. In vitro experiments confirmed that PLXNA3 is highly expressed in CRC cell lines and that its knockdown significantly suppresses cell proliferation and migration. CONCLUSION: In this study, experimental evidence is provided regarding the promotion of proliferation and migration of CRC by PLXNA3, complementing existing computational predictions. These findings support the role of PLXNA3 as a functionally validated oncogene in CRC and as a candidate for further therapeutic investigation.
Ling et al. (2026) studied this question.