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// Shau-Hsuan Li 1 , Hung-I Lu 2 , Alice Y.W. Chang 3 , Wan-Ting Huang 4 , Wei-Che Lin 5 , Ching-Chang Lee 6 , Wan-Yu Tien 1 , Ya-Chun Lan 1 , Hsin-Ting Tsai 3, 7, 8 , Chang-Han Chen 8, 9, 10 1 Department of Hematology-Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 2 Department of Thoracic & Cardiovascular Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 3 Institute of Physiology, National Cheng Kung University, Tainan, Taiwan 4 Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 5 Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan 6 Department of Gastroenterology, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan 7 Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan, Taiwan 8 Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan 9 Department of Applied Chemistry, and Graduate Institute of Biomedicine and Biomedical Technology, National Chi Nan University, Taiwan 10 Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan Correspondence to: Chang-Han Chen, email: chench7@gmail.com Keywords: esophageal cancer, squamous cell carcinoma, AT1R, angiotensin II, mTOR Received: March 12, 2016 Accepted: August 11, 2016 Published: August 24, 2016 ABSTRACT Background: The aim of this study was to investigate the effects of the angiotensin II/ angiotensin II type I receptor (AT1R) and angiotensin II type II receptor (AT2R) signaling pathway in esophageal squamous cell carcinoma (ESCC). Methods: Immunohistochemistry was performed to evaluate the expression levels of AT1R and AT2R in tissues from 152 surgically resected ESCC patients, and those expression levels were then correlated with treatment outcomes. The angiotensin II/AT1R/AT2R signaling pathway and its biological effects in the context of ESCC were investigated in vitro and in vivo . Results: In human samples, AT1R overexpression was univariately associated with inferior overall survival and remained multivariately independent (hazard ratio=1.812). In vitro , angiotensin II stimulated the growth of ESCC cells in a dose-dependent manner. Treatment with irbesartan or AT1R-RNAi knockdown but not treatment with PD123319 significantly decreased the level of angiotensin II-induced ESCC cell proliferation. Angiotensin II also caused mTOR activation in a dose-dependent manner, and everolimus or mTOR-RNAi knockdown significantly suppressed the level of angiotensin II-induced ESCC cell proliferation. Furthermore, AT1R-RNAi knockdown suppressed the activation of mTOR. Clinically, AT1R expression was also correlated with phosphorylated mTOR expression. In a xenograft model, local angiotensin II injection enhanced tumor growth, and this effect could be decreased by treatment with irbesartan or everolimus. In a 4-NQO-induced-ESCC murine model, irbesartan significantly decreased the incidence of esophageal tumor. Conclusions: These findings suggest that AT1R overexpression is an independent adverse prognosticator for patients with ESCC and that angiotensin II/AT1R signaling stimulates ESCC growth, in part through mTOR activation. |
