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Nan-bo Liu,1,* Jun-hua Zhang,2,* Yu-fan Liu,1,* Jun Li,3,* Zhen-zhong Zhang,1 Ji-wei Li,1 Wen-yue Liu,1 Chen Huang,1,4 Tao Shen,5 Cheng-wei Gu,6 Dong-yun Gao,7 Xia Wu,8 Xu Wu1 1Department of Thoracic Surgery, 2Department of Anesthesiology, Nanfang Hospital, Southern Medical University, 3Department of Thoracic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, 4Department of Thoracic Surgery, Fujian Provincial Hospital, Fuzhou, 5Department of Thoracic Surgery, Jiangmen Central Hospital, Jiangmen, 6Department of Thoracic Surgery, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, 7Department of Oncology, Dongtai People's Hospital, Dongtai, 8Department of Breast Cancer, Affiliated Hospital, Academy of Military Medical Sciences, Beijing, People's Republic of China *These authors contributed equally to this work Objective: The disheveled, Egl-10, and pleckstrin (DEP) domain containing mammalian target of rapamycin (mTOR)-interacting protein (DEPTOR) is a binding protein containing mTOR complex 1 (mTORC1), mTOR complex 2 (mTORC2), and an endogenous mTOR inhibitor. DEPTOR shows abnormal expressions in numerous types of solid tumors. However, how DEPTOR is expressed in esophageal squamous cell carcinoma (ESCC) remains elusive. Methods: The expression of DEPTOR in 220 cases of ESCC and non-cancerous adjacent tissues was detected by immunohistochemistry. DEPTOR levels in ESCC and paired normal tissue were quantified using reverse transcription-polymerase chain reaction and Western blot analysis to verify the immunohistochemical results. The relationship between DEPTOR expression and the clinicopathological features of ESCC was analyzed based on the results of immunohistochemistry. Finally, we analyzed the relationship between DEPTOR expression and the prognosis of patients with ESCC. Results: Immunohistochemical staining showed that the expression rate of DEPTOR in ESCC tissues was significantly increased. DEPTOR mRNA and protein expression was significantly higher in ESCC tissues than in normal adjacent esophageal squamous tissues. High DEPTOR expression was significantly correlated with regional lymph node status in the TNM stage of patients with ESCC. Kaplan–Meier survival curves showed that the rate of overall survival was significantly lower in patients with high DEPTOR expression than in those with low DEPTOR expression. Additionally, high DEPTOR expression was an independent prognostic predictor for ESCC patients. Conclusion: High DEPTOR expression is an independent prognostic biomarker indicating a worse prognosis for patients with ESCC. Keywords: DEPTOR, ESCC, prognosis