抑制胆囊癌细胞内Janus激酶／信号转导与转录激活子1信号通路以下调吲哚胺2，3双加氧酶表达的意义  

Suberoylanilide hydroxamic acid （SAHA） suppresses JAK/STAT1 signal pathway to down-regulate the expression of indoleamine 2, 3-dioxygenase in gallbladder carcinoma cells

作　　者：张鹏[1] 江冠民[2] 高剑[1] 李玲玲[2] 杜军[2] 焦兴元[1] 石景森[3] 

机构地区：[1]广州医学院第二附属医院肝胆外科,510260 [2]中山大学药学院微生物与生化制药实验室 [3]西安交通大学医学院第一附属医院普外科

出　　处：《中华肝胆外科杂志》2011年第10期833-837,共5页Chinese Journal of Hepatobiliary Surgery

基　　金：国家自然科学基金资助（30840096）

摘　　要：目的探讨调控胆囊癌细胞内Janus激酶（JAK）／信号转导与转录激活子1（STAT1）信号通路抑制吲哚胺2，3双加氧酶（IDO）表达的作用机制，为解除胆囊癌生物治疗中肿瘤产生的免疫耐受提供理论依据。方法应用γ-干扰素和组蛋白去乙酰化酶抑制剂SAHA处理胆囊癌SGC-996细胞。Western blot方法检测IDO、STAT1以及干扰素调节转录因子1（IRF-1）的表达。用细胞免疫组化和激光共聚焦显微镜观察STATl的人核情况，转染和荧光素酶报告基因分析7激活序列（GAS）和干扰素刺激反应元件（ISRE）的活性。结果胆囊癌细胞中IFN-γ刺激IDO的表达呈剂量和时间依赖性。SAHA抑制IDO的表达呈剂量依赖性。SAHA抑制STAT1的磷酸化和入核，抑制IFN-γ促进的GAS、ISRE和IRF-1的活性。结论抑制人胆囊癌细胞中JAK／STAT1信号通路可导致IDO表达下降，表明调控JAK／STAT1信号通路可能会解除胆囊癌生物治疗中肿瘤产生的免疫耐受。Objective To investigate the mechanism on JAK/STAT1 signal pathway in SAHA down-regulation of indoleamine 2, 3-dioxygenase （IDO） in gallbladder carcinoma cells. Methods We treated gallbladder carcinoma SGC-996 cells with IFN-γ and SAHA. Western blotting was used to detect the expression of IDO, signal transducer and activator of transcription ] （STAT1） phosphorylation and interferon regulatory factor genes 1 （IRF-1）. Confocal microscopy analysis was used to detect STAT1 translocation. Transient transfections and reporter genes assay was used in detecting the acti vation of γ-activated sites （GAS） and interferon stimulated response elements （ISRE）. Results IDO expressed in SGC-996 cells in dose and time-dependent manners when stimulated with IFN-γ. SAHA down-regulated the expression of IDO induced by IFN-γ in a dose-dependent manner. SAHA blocked the expression of IRF-I induced by IFN-γ. SAHA inhibited the IFN γ-induced STAT1 phosphorylation and nuclear translocation. SAHA down-regulated IFN-γ-induced activation of GAS and ISRE. Conclusions SAHA may down-regulate IDO expression through inhibiting the activation of members in JAK/STAT1 signal pathway. This may provide a new immunotherapeutic strategy to break tumor immune tolerance in gallbladder carcinoma.

关 键 词：吲哚胺2 3-双加氧酶 胆囊癌 组蛋白去乙酰化酶抑制剂 免疫耐受 

分 类 号：R735.8[医药卫生—肿瘤]