BackgroundPreoperative chemoradiation combined with surgery has been of focus recently in order to improve prognosis in esophageal squamous cell carcinoma (ESCC) patients. Finding biological markers that may assist in predicting the therapeutic effect of chemoradiation may benefit the treatment effect. In this study, the role of RUNX3 in the formation of cisplatin resistance in ESCC was examined.MethodsThe study enrolled 103 stage IIa–IIIb ESCC patients who had undergone esophagectomy. RUNX3 expression in ESCC tissue was detected.ResultsA higher expression of RUNX3 in ESCC patients correlated with a more sensitive response to cisplatin‐based chemotherapy. A consistently lower expression of RUNX3 was found in the ESCC tissues of patients who agreed to perioperative chemotherapy compared with patients who had undergone no preoperative treatment. A lower RUNX3 expression in cisplatin‐resistant ESCC cell lines, Eca109 and TE‐1, was observed compared with parental cell lines. Heterologous RUNX3 expression significantly suppressed cisplatin resistance in Eca109 and TE‐1, both in vitro and vivo. Meanwhile, heterologous RUNX3 expression could inhibit growth and induce apoptosis in cisplatin resistant Eca109 and TE‐1 cell lines in vitro. Remarkable inhibition of the Akt pathway was observed in heterologous RUNX3 expression in Eca109 and TE‐1. Silencing Akt1 could reverse cisplatin resistance in Eca109 and TE‐1.ConclusionOur results confirmed that a loss of RUNX3 in ESCC may contribute to cisplatin‐resistance. RUNX3 could reverse cisplatin resistance via suppression of the Akt pathway in ESCC patients.