TY - JOUR
T1 - Reciprocal androgen receptor/interleukin-6 crosstalk drives oesophageal carcinoma progression and contributes to patient prognosis
AU - Dong, Hongmei
AU - Xu, Jinjin
AU - Li, Weiwei
AU - Gan, Jinfeng
AU - Lin, Wan
AU - Ke, Jierong
AU - Jiang, Jiali
AU - Du, Liang
AU - Chen, Yuping
AU - Zhong, Xueyun
AU - Zhang, Dianzheng
AU - Yeung, Sai Ching Jim
AU - Li, Xiaotao
AU - Zhang, Hao
N1 - Funding Information:
We thank Chen Ke and Lin Zheng for technical assistance. This work was supported in part by funding from the National Natural Science Foundation of China (grant Nos 81071736 and 81572876 to HZ); the Collaborative and Creative Center, Molecular Diagnosis and Personalized Medicine, Shantou University, Guangdong Province (grant No 201412); and the Department of Education, Guangdong Government under the Top-tier University Development Scheme for Research and Control of Infectious Diseases (grant No 201421).
Publisher Copyright:
Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
PY - 2017/3/1
Y1 - 2017/3/1
N2 - 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.
AB - 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.
KW - chronic inflammation
KW - cytokine
KW - male prevalence
KW - oesophageal squamous cell carcinoma
KW - positive feedback loop
KW - tobacco exposure
KW - unhealthy lifestyle
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U2 - 10.1002/path.4839
DO - 10.1002/path.4839
M3 - Article
C2 - 27801498
AN - SCOPUS:85012960880
SN - 0022-3417
VL - 241
SP - 448
EP - 462
JO - Journal of Pathology
JF - Journal of Pathology
IS - 4
ER -