A tumor-promoting role of metallothionein 2A in glioma

Background Despite great efforts devoted to glioma research, most patients still suffer from poor clinical outcomes, largely due to a poor understanding of the underlying mechanisms. Methods This work analyzed MT2A expression and prognostic relevance using two independent public RNA-seq cohorts, the Chinese Glioma Genome Atlas (CGGA, n = 325) and The Cancer Genome Atlas (TCGA, n = 656). Prognostic value was assessed by Kaplan-Meier survival analysis, Cox regression, and a LASSO-based risk score derived from MT2A-related genes rather than MT2A alone. Gene set enrichment analysis (GSEA) was performed to identify associated signaling pathways. Functionally, three siRNAs were screened for MT2A knockdown in U251 cells, the most effective siRNA was used for downstream assays, and MT2A was overexpressed in U87 cells via plasmid transfection. The biological phenotypes evaluated included proliferation, clonogenic growth, migration, invasion, cell-cycle distribution, apoptosis under cisplatin challenge, EMT-associated marker expression, and xenograft growth in vivo. Results Our data identify MT2A as a candidate contributor to glioma malignancy and poor prognosis. Genome-wide analyses showed marked elevation of MT2A expression in glioma, with clear associations with unfavorable clinicopathological characteristics and shorter overall survival in both CGGA and TCGA cohorts. In addition, an MT2A-related gene risk score stratified patients into prognostic risk groups across training, validation, and external validation datasets. Consistently, experimental investigation indicated a tumor-promotive role of MT2A in glioma, as reflected by increased cell proliferation, clonogenicity, migration, and invasion in vitro, together with altered cell-cycle progression, reduced cisplatin-induced apoptosis, and EMT-associated molecular changes. Ectopic expression of MT2A also conferred a growth advantage in a U87 xenograft mouse model. Conclusions These findings support the potential prognostic significance of MT2A in glioma and suggest that MT2A may represent a candidate biological vulnerability requiring further mechanistic and therapeutic validation.