The impact of p16 hypermethylation on accumulation of abnormally expressed proteins in the p53-MDM2 pathway, along with the observed concomitant accumulation of p53 with either MDM2 overexpression or decreased p16 expression, suggests a possible cross-talk of the involved pathways in ESCC development in northeastern Iran. Here, TP53 is linked to esophageal squamous cell carcinoma.