In this study, we revealed that the miR-200b-ZEB1/2 axis contributes to the pathobiology of ESCC via an EMT-independent mechanism, whereas suppression of the Kindlin-2-integrin β1-AKT regulatory axis is an alternative mechanism underlying the tumor suppressor function of miR-200b in ESCC. Here, AKT1 is linked to esophageal squamous cell carcinoma.