基于蛋白质组学的IL-6R/STAT3信号通路与垂体裸细胞瘤侵袭性的相关性研究  

Correlation of IL-6R/STAT3 signaling with invasiveness of pituitary null cell adenomas： A study based on proteomics

作　　者：冯洁[1] 于升远 洪礼传[1] 李储忠[1] 赵斯达 李桂玲 杨晶晶[1] 万虹[1] 张亚卓[1] 

机构地区：[1]北京市神经外科研究所,首都医科大学,100050

出　　处：《中华神经外科杂志》2017年第12期1268-1272,共5页Chinese Journal of Neurosurgery

基　　金：公益性行业科研专项资助（201402008）;国家高技术研究发展计划（863计划）项目（2014AA020610）;北京市医院管理局‘青苗’计划（QML20160506）

摘　　要：目的 基于垂体腺瘤蛋白质组学研究,探讨IL-6 R/STAT3信号通路与垂体裸细胞瘤侵袭性的相关性.方法 本研究取材于首都医科大学附属北京天坛医院神经外科行手术治疗的45例垂体裸细胞瘤患者,正常垂体组织取材于3例交通意外后尸体捐献者.采用超高效液相色谱和蛋白质质谱分析侵袭性和非侵袭性垂体裸细胞瘤组织之间的差异蛋白质,进一步通过生物信息分析方法识别与垂体裸细胞瘤侵袭相关的信号通路,之后采用实时定量PCR（qPCR）和免疫组化方法验证该信号通路在侵袭性和非侵袭性垂体裸细胞瘤组织中的表达情况.结果 蛋白质质谱分析结果显示：283个蛋白质在侵袭性和非侵袭性垂体裸细胞瘤中的表达差异有统计学意义（均P ＜0.05）.在侵袭性垂体裸细胞瘤中,表达上调的蛋白质有182个,下调的有101个.生物信息分析结果显示：8个经典通路存在共上调或共下调,其中IL-6R/STAT3信号通路与垂体裸细胞瘤侵袭性相关.qPCR结果显示：IL-6R、JAK2和STAT3基因在侵袭性垂体裸细胞瘤中的表达量（分别为2.2、2.8、4.3）显著高于非侵袭性裸细胞瘤（分别为1.7、1.7、2.9,均P＜0.05）.免疫组化结果显示：IL-6R、JAK2、STAT3、p-STAT3和MMP9在侵袭性裸细胞瘤中的染色强度评分（分别为9.2分、8.6分、9.7分、10.5分和9.8分）较非侵袭性裸细胞瘤（分别为5.8分、5.3分、5.7分、5.2分和4.1分）高（均P＜0.05）.结论 IL-6R/STAT33信号通路与垂体裸细胞瘤侵袭性相关,且IL-6R/STAT3信号通路可能通过上调MMP9的表达在垂体裸细胞瘤的侵袭中发挥重要作用.Objective To identify the relationship of IL-6R/STAT3 signaling to invasiveness of pituitary null cell adenomas by the study of proteomics.Methods In this study,specimens were collected from 45 cases of pituitary null cell adenomas which were surgical treated at Department of Neurosurgery,Beijing Tiantan Hospital,Capital Medical University.Normal pituitary tissues were collected from 3 body donors who died from traffic accidents.Different proteins between invasive and non-invasive null cell adenomas were determined by nano liquid chromatography tandem mass spectrometry （nano LC-MS/MS） and quantitative proteomics analysis.The signaling pathway related to invasive of null cell adenomas was identified by bioinformatic analysis.The gene expression levels of the signaling pathway was confirmed by qPCR （quantitative polymerase chain reaction） and immunohistochemistry （IHC） in invasive pituitary tumors and non-invasive null cell adenomas.Results A total of 283 differentially expressed proteins （P 〈 0.05） were identified between invasive and non-invasive pituitary null cell adenomas.Among those,182 and 101 were up-regulated and down-regulated in invasive pituitary null cell adenomas,respectively.The bioinformatic analysis demonstrated that 8 canonical pathways were differentially expressed between normal pituitary glands and pituitary null cell adenomas.IL-6R/STAT3 signaling was related to invasiveness of pituitary null cell adenomas.The IL-6R,JAK2 and STAT3 mRNA expression levels in invasive null cell adenomas （2.2,2.8 and 4.3,respectively） were significantly higher than those in non-invasive null cell adenomas （1.7,1.7,2.9,respectively） based on the results of qPCR （P 〈 0.05）.The values of staining intensity of IL-6R,JAK2,STAT3,p-STAT3 and MMP9 （9.2,8.6,9.7,10.5 and 9.8,respectively） were significantly increased in invasive null cell adenomas compared with those in non-invasive null cell adenomas （5.8,5.3,5.7,5.2 and 4.1,respectively） according to the IHC data.Conclusion The IL-6

关 键 词：垂体腺瘤 肿瘤浸润 蛋白质组学 信号通道 IL-6R/STAT3 

分 类 号：R736.4[医药卫生—肿瘤]