NSUN2 silencing attenuated PI3K/AKT and ERK/MAPK signaling via decreasing both m5C and mRNA levels of GRB2, while GRB2 overexpression reversed the inhibition of malignant cellular phenotypes in NSUN2-depleted cells, suggesting that GRB2 is a key mediator of malignancy induced by abnormal NSUN2-meidated m5C modification in ESCC. This evidence concerns the gene GRB2 and esophageal squamous cell carcinoma.