Comprehensive pan-cancer analysis of MEX3 family genes reveals prognostic and immune-related significance in human cancers

The MEX3 family of RNA-binding E3 ubiquitin ligases has been implicated in cancer, but its pan-cancer molecular and clinical significance remains unclear. Here, we systematically characterized MEX3A, MEX3B, MEX3C and MEX3D across human cancers using TCGA and GTEx transcriptomic data, survival analyses, genomic alteration and DNA methylation profiles, immune infiltration assessments, and protein-protein interaction and functional enrichment analyses. MEX3A, MEX3C and MEX3D were broadly upregulated in tumors, whereas MEX3B showed more heterogeneous expression patterns. Elevated MEX3 expression exhibited cancer-and gene-specific prognostic associations, with consistently unfavorable outcomes for all four family members in adrenocortical carcinoma and mesothelioma after adjustment for clinical covariates. Genomic alterations were dominated by amplification, mutation or deep deletion depending on tumor context, while DNA methylation was generally inversely associated with MEX3 expression. Immune analyses revealed context-dependent associations with immune and stromal scores, cancer-associated fibroblasts, and diverse immune-cell populations, with recurrent positive correlations with Th2-cell infiltration. Network and enrichment analyses linked MEX3-associated genes to RNA metabolism, translational regulation, ribonucleoprotein granules, RNA binding, ferroptosis, viral carcinogenesis and RNA degradation. These findings define shared and tumor-specific features of MEX3 dysregulation and support their potential value as prognostic biomarkers and modulators of the tumor microenvironment.