title: Angiotensin II type I receptor (AT1R) is an independent prognosticator of esophageal squamous cell carcinoma and promotes cells proliferation via mTOR activation.
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.
authors: Department of Hematology-Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors: Shau-Hsuan
authors: SH
authors: Li
authors: Department of Thoracic & Cardiovascular Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors: Hung-I
authors: HI
authors: Lu
authors: Institute of Physiology, National Cheng Kung University, Tainan, Taiwan.
authors: Alice Y W
authors: AY
authors: Chang
authors: Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors: Wan-Ting
authors: WT
authors: Huang
authors: Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors: Wei-Che
authors: WC
authors: Lin
authors: Department of Gastroenterology, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan.
authors: Ching-Chang
authors: CC
authors: Lee
authors: Department of Hematology-Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors: Wan-Yu
authors: WY
authors: Tien
authors: Department of Hematology-Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors: Ya-Chun
authors: YC
authors: Lan
authors: Institute of Physiology, National Cheng Kung University, Tainan, Taiwan.|Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan, Taiwan.|Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
authors: Hsin-Ting
authors: HT
authors: Tsai
authors: Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.|Department of Applied Chemistry, and Graduate Institute of Biomedicine and Biomedical Technology, National Chi Nan University, Taiwan.|Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: Chang-Han
authors: CH
authors: Chen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D049109:Cell Proliferation; D004938:Esophageal Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D064593:Heterografts; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008875:Middle Aged; D011379:Prognosis; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: AT1R; angiotensin II; esophageal cancer; mTOR; squamous cell carcinoma