Reciprocal androgen receptor/interleukin-6 crosstalk drives oesophageal carcinoma progression and contributes to patient prognosis
Reciprocal androgen receptor/interleukin-6 crosstalk drives oesophageal carcinoma progression and contributes to patient prognosis
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雄激素受体/白细胞介素 6 的相互串扰驱动食管癌进展并有助于患者预后
DOI：
10.1002/path.4839
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发表时间：
2017-03-01
影响因子：
7.3
通讯作者：
Zhang, Hao
中科院分区：
文献类型：
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作者：
Dong, Hongmei;Xu, Jinjin;Zhang, Hao
食道鳞状细胞癌(ESCC)是一种主要的致死性消化道恶性肿瘤，具有明显的性别差异。阐明雄激素受体(AR)的功能和调控途径将有助于我们更好地了解食道癌的进展，从而促进食管鳞癌的个性化治疗。在这里，我们报告的证据表明，AR是ESCC癌症进展过程中炎症信号的关键介质。在使用烟草的ESCC患者中，AR的高表达与总体生存率较低有关，而在不使用烟草的ESCC患者中，AR的高表达与总体生存率不相关。AR功能的增强和丧失分别通过改变细胞周期进程促进和抑制ESCC细胞的生长。在携带人ESCC移植瘤的小鼠中，沉默AR表达抑制了肿瘤生长，而AR过表达促进了不同雄激素状态(雄性、雌性和去势雄性)小鼠的肿瘤生长。芯片分析表明，炎症细胞因子白介素6(IL6)是食管鳞癌中一个重要的AR靶基因。通过直接与IL6启动子结合，AR促进IL6转录，IL6进而激活AR的表达，从而形成一个相互调节的回路来维持食管癌中STAT3的致癌信号。此外，AR和IL6在人ESCC中的高表达预示着吸烟者的不良临床结局。综上所述，这些数据证实AR促进ESCC生长，并与患者预后不良有关。IL6和AR之间正反馈回路的发现弥合了与生活方式因素相关的炎症、性别差异和食道癌之间的知识差距。版权所有(C)2016年大不列颠和爱尔兰病理学会。作者：John Wiley&Sons，Ltd.
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 (C) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.