汕头大学医学院揭秘食管癌性别差异
近日,汕头大学医学院张灏课题组发现雄性激素受体AR信号通路在不良生活方式导致的肿瘤持续炎症反应中起重要调节作用。相关研究发表在国际期刊《病理学》杂志。


食管癌特点之一是男性高发并且预后比女性更差。事实上,包括食管癌在内的诸多恶性肿瘤都有男性高发并且预后更差的特点,但这种性别差异背后的机制一直是个谜,在临床上缺乏针对性的个体化防治方案。

据了解,张灏课题组通过对多个病人样本进行队列生存分析后发现吸烟病人的AR表达水平与预后密切相关,同时体外和体内实验表明AR表达异常能够促进肿瘤生长。

鉴于吸烟等男性为主的生活行为方式可以导致细胞慢性炎症反应,研究人员通过芯片筛选、生物信息学分析和分子生物学等发现炎症因子IL-6是受AR转录调控的新靶基因。

之后进一步发现AR和IL-6形成反馈环,通过反复互作持续激活STAT3等癌基因通路进而促进肿瘤。研究表明,AR在吸烟等生活方式导致的癌症相关不可逆炎症中起介导和桥梁作用。

该研究从一个角度揭开了食管癌性别差异之谜,为生活行为因素与体内基因互作在癌症中的重要性,提供了新证据,为个性化预防和干预食管癌提供了新选择。

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  • Reciprocal androgen receptor/interleukin-6 crosstalk drives oesophageal carcinoma progression and contributes to patient prognosis

    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.

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