On the whole, our findings demonstrate that hub genes, CDK1, VEGFA, PRDM10, RUNX1, CDK6, HSP90AA1, MYC, EGR1, and SOX2 regulates ESCC cells via multiple networks involved in various signaling contexts, which would provide novel therapeutic strategies for ESCC patients. This evidence concerns the gene VEGFA and esophageal squamous cell carcinoma.