title: Reciprocal androgen receptor/interleukin-6 crosstalk drives oesophageal carcinoma progression and contributes to patient prognosis.
abstract: Oesophageal squamous cell carcinoma (ESCC), a leading lethal malignancy of the digestive tract, is characterized by marked gender disparity. Clarifying the roles of the function and regulatory pathway of the androgen receptor (AR) will improve our understanding of oesophageal cancer progression, thereby facilitating the personalized management of ESCC. Here we report evidence to show that AR is a key mediator of inflammatory signals in ESCC cancer progression. High AR expression was associated with poor overall survival in tobacco-using ESCC patients but not in ESCC patients not using tobacco. A gain and loss of AR function enhanced and repressed ESCC cell growth, respectively, by altering cell cycle progression. In mice bearing human ESCC xenografts, silencing AR expression attenuated tumour growth, whereas AR overexpression promoted tumour growth in mice of different androgen statuses (male, female, and castrated male). Array assays revealed that the inflammatory cytokine interleukin-6 (IL6) is a prominent AR target gene in ESCC. By directly binding to the IL6 promoter, AR enhances IL6 transcription, and IL6 can in turn activate AR expression, thus forming a reciprocal regulatory circuit to sustain STAT3 oncogenic signalling in ESCC. Moreover, high expression levels of both AR and IL6 in human ESCC predict poor clinical outcome in tobacco users. Together, these data establish that AR promotes ESCC growth and is associated with poor patient prognosis. The discovery of a positive feedback loop between IL6 and AR bridges the knowledge gaps among lifestyle factor-associated inflammation, gender disparity, and oesophageal carcinoma. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors: Cancer Research Center, Shantou University Medical College, Shantou, Guangdong, PR China.
authors: Hongmei
authors: H
authors: Dong
authors: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, Shanghai, PR China.
authors: Jinjin
authors: J
authors: Xu
authors: Cancer Research Center, Shantou University Medical College, Shantou, Guangdong, PR China.
authors: Weiwei
authors: W
authors: Li
authors: Cancer Research Center, Shantou University Medical College, Shantou, Guangdong, PR China.
authors: Jinfeng
authors: J
authors: Gan
authors: Cancer Research Center, Shantou University Medical College, Shantou, Guangdong, PR China.
authors: Wan
authors: W
authors: Lin
authors: Cancer Research Center, Shantou University Medical College, Shantou, Guangdong, PR China.
authors: Jierong
authors: J
authors: Ke
authors: Cancer Research Center, Shantou University Medical College, Shantou, Guangdong, PR China.
authors: Jiali
authors: J
authors: Jiang
authors: Cancer Research Center, Shantou University Medical College, Shantou, Guangdong, PR China.
authors: Liang
authors: L
authors: Du
authors: Department of Thoracic Surgery, Affiliated Cancer Hospital of Shantou University Medical College, Shantou, PR China.
authors: Yuping
authors: Y
authors: Chen
authors: Department of Pathology, Jinan University Medical College, Guangzhou, PR China.
authors: Xueyun
authors: X
authors: Zhong
authors: Department of Biochemistry and Molecular Biology and Center for Chronic Disorders of Aging, Philadelphia College of Osteopathic Medicine, Philadelphia, USA.
authors: Dianzheng
authors: D
authors: Zhang
authors: Department of Emergency Medicine and Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors: Sai-Ching Jim
authors: SJ
authors: Yeung
authors: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, Shanghai, PR China.|Department of Molecular and Cellular Biology, The Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
authors: Xiaotao
authors: X
authors: Li
authors: Cancer Research Center, Shantou University Medical College, Shantou, Guangdong, PR China.|Department of Biotherapy, Affiliated Cancer Hospital of Shantou University Medical College, Shantou, PR China.|Tumor Tissue Bank, Affiliated Cancer Hospital of Shantou University Medical College, Shantou, PR China.
authors: Hao
authors: H
authors: Zhang
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015331:Cohort Studies; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D014026:Nicotiana / Q000009:adverse effects
chemical_list: C410798:AR protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D012333:RNA, Messenger; D011944:Receptors, Androgen; D019947:Receptors, Interleukin-6
keywords: chronic inflammation; cytokine; male prevalence; oesophageal squamous cell carcinoma; positive feedback loop; tobacco exposure; unhealthy lifestyle