Bioinformatic analysis and experimental validation of the function of mitogen-activated protein kinase in esophageal cancer

Esophageal cancer remains a highly lethal malignancy with limited therapeutic options. Although MAP3K family members regulate proliferation and differentiation, their clinical significance and functional roles in esophageal cancer remain poorly understood. We performed integrated multi-omics analyses including transcriptomic profiling, DNA methylation assessment, and single-cell RNA sequencing to systematically characterize MAP3K family members in esophageal cancer. WGCNA and regulatory network analyses identified downstream targets of MAP3K11. Functional studies were conducted in esophageal cancer cell lines to validate findings. We identified MAP3K2, MAP3K11, and MAP3K13 as significantly upregulated in esophageal cancer tissues and found that elevated MAP3K11 expression independently predicted poorer prognosis and associated with advanced metastatic disease. Single-cell analysis revealed preferential MAP3K11 enrichment in endothelial cells and uncovered a distinct MAP3K11-high malignant subpopulation exhibiting substantially enhanced communication with cancer-associated fibroblasts. MAP3K11 regulated an extensive gene network involved in apoptosis and cell junction regulation, with Rad21 emerging as a critical downstream effector. Functional studies demonstrated that MAP3K11 suppression markedly inhibited cancer cell proliferation and migration while promoting apoptosis, effects that were substantially reversed by Rad21 restoration. MAP3K11 functions as a key driver of esophageal cancer progression through the Rad21 axis and represents a promising candidate biomarker for diagnosis and prognosis. The identification of MAP3K11-mediated tumor-stromal crosstalk provides novel mechanistic insights into esophageal cancer microenvironmental dynamics.