胆管癌脾酪氨酸激酶表达增高对肿瘤微环境巨噬细胞M2型极化的影响  

Aberrant SYK expression in cholangiocarcinoma and its effect on M2 macrophage polarization in tumor microenvironment

作　　者：袁辉 林泽龙 胡敏[2] 蒋煜川 刘珂 曲辰 洪健 YUAN Hui;LIN Ze-long;HU Min;JIANG Yu-chuan;LIU Ke;QU Chen;HONG Jian(Cancer Center of Integrated Hospital of Traditional Chinese Medicine,Southern Medical University,Guangzhou 510315,China;Department of Hepatobiliary Surgery,The First Affiliated Hospital of Jinan University,Guangzhou 510632,China;Department of Pharmacy,College of Pharmacy,Jinan University,Guangzhou 510632,China;Department of Pathophysiology,School of Medicine,Jinan University,Guangzhou 510632,China)

机构地区：[1]南方医科大学中西医结合医院肿瘤中心,广东广州510315 [2]暨南大学附属第一医院肝胆外科,广东广州510632 [3]暨南大学药学院药学系,广东广州510632 [4]暨南大学基础医学院病理生理系,广东广州510632

出　　处：《中国病理生理杂志》2020年第6期961-968,共8页Chinese Journal of Pathophysiology

基　　金：国家自然科学基金资助项目(No.81672320,No.81871987);广州市羊城学者项目(No.1201561579);广州市科技计划项目(No.201704020128)。

摘　　要：目的:研究脾酪氨酸激酶(SYK)在大鼠和小鼠胆管癌演变进程和人胆管癌组织中的表达情况,并探讨其表达对肿瘤巨噬细胞M2型极化的影响。方法:分别构建大鼠和小鼠的胆管癌模型(SD大鼠:日常饮用水中加入硫代乙酰胺;BALB/c小鼠:左中位胆管结扎联合二乙基亚硝胺给药),采用免疫组织化学法检测胆管癌演变进程中肝脏胆管病变组织和人胆管癌标本的SYK表达及M2型巨噬细胞(CD163)的浸润情况,并分析相关性;将10只持续24周饮用含硫代乙酰胺饮用水的SD大鼠随机分为对照组(n=5)和SYK抑制剂组(n=5),治疗4周后处死大鼠,观察SYK抑制剂对肿瘤生长及巨噬细胞极化的影响。结果:大鼠和小鼠发生肝脏胆管增生、胆管异型增生(或胆管瘤)和胆管癌病变的时间窗不同(大鼠分别于第9、12和24周时出现;小鼠分别于第12、16和28周时出现)。在大鼠和小鼠的肝脏胆管病变组织中,均随着胆管癌的演变进展,SYK表达逐渐升高(P<0. 01),伴有M2型巨噬细胞浸润数量增多,而M1型巨噬细胞数量减少(P<0. 01);在人胆管癌组织中,SYK表达与CD163阳性细胞数(M2型巨噬细胞浸润数量)均显著升高(P<0. 01),二者呈正相关(r=0. 57,P<0. 01)。在大鼠胆管癌模型中,与对照组相比,SYK抑制剂组肿瘤数量减少(P<0. 01),M2型巨噬细胞数量减少(P<0. 01)。结论:大/小鼠胆管癌模型中SYK异常表达随着胆管癌的发生发展逐渐升高,可能通过影响巨噬细胞M2型极化促进肿瘤进展;SYK抑制剂可以抑制大鼠胆管癌的肿瘤生长和巨噬细胞M2型极化。AIM:To investigate the expression of spleen tyrosine kinase(SYK)in 2 murine cholangiocarcino⁃ma(CCA)progressive models and human CCA tissues,and to explore the effects of SYK expression on the polarization of M2 macrophages.METHODS:SD rats were given drinking water containing thioacetamide(TAA)daily.BALB/c mice were treated with left median bile duct ligation combined with diethylnitrosamine(DEN)administration.The expression of SYK and M2 macrophage infiltration(CD163)in the animals and human CCA tissues were detected by immunohisto⁃chemistry,and their correlation was analyzed.Ten SD rats,which were given drinking water containing TAA daily for 24 weeks,were randomly divided into control group(n=5)and SYK inhibitor group(n=5).After the rats received SYK in hibitor through gavage for 4 weeks,the effects of SYK inhibitor on tumor growth and macrophage polarization were ana⁃lyzed.RESULTS:The hepatic bile duct hyperplasia,dysplasia(or cholangioma),and CCA occurred at different time points in the rats and mice.During the development of CCA,SYK expression was gradually increased(P<0.01),accom⁃panied by enhanced infiltration of M2 macrophages,while the M1 macrophages were decreased in the hepatic bile duct tis⁃sues(P<0.01).SYK and CD163 expression levels were significantly up-regulated(P<0.01),and a positive correlation(r=0.57,P<0.01)in human CCA tissues was observed.In the rat CCA model,the number of tumor nodules and infiltra⁃tion of M2 macrophages in SYK inhibitor group were decreased compared with its control group(P<0.01).CONCLU⁃SION:In the murine CCA models,SYK expression was progressively increased during the evolution of CCA,which may promote tumor progression via the polarization of M2 macrophages,and SYK inhibitor effectively inhibits the tumor growth and M2 macrophage polarization in the rat CCA model.

关 键 词：胆管癌 脾酪氨酸激酶 M2型巨噬细胞极化 靶向治疗 

分 类 号：R735.8[医药卫生—肿瘤] R363.2[医药卫生—临床医学]