中国科技核心期刊
CN:31-1600/Q
ISSN:1004-0374
“健康与疾病的免疫”国际学术研讨会通知      关于有网站冒充本刊网站的声明
《生命科学》 2010, 22(11): 1097-1101
乙肝病毒表面抗原持续表达的新致病机制
赵 超,田晓晨,闻玉梅*
复旦大学上海医学院教育部/卫生部医学分子病毒学重点实验室,复旦大学生物医学研究院,上海200032
摘 要:乙型肝炎表面抗原(HBsAg)持续阳性是控制乙肝中难以解决的重大问题。本研究通过揭示HBsAg致病机制的基础研究,寻找抑制或清除HBsAg的新途径。通过建立有可比性的HBsAg转基因鼠和稳定表达细胞系及相应对照,进行比较转录组学和蛋白质组学研究,发现了HBsAg在HBV慢性感染中的一些新致病机制。其中包括:HBsAg促进肝细胞内CypA分泌,后者可趋化炎症细胞在HBsAg阳性灶周围浸润;在细胞模型中,HBsAg分泌可引起胞内GRP78蛋白下降,导致肝细胞抗凋亡能力减弱;发现HBsAg在细胞中可上调截短的LEF1基因的表达,缺乏活化全长LEF1促成瘤和增殖活性;而肝癌组织中LEF1则倾向于核内分布,并活化Wnt下游基因Cyclin D1与c-myc,有促肿瘤活性。在转基因鼠和细胞模型中都发现了物质和能量代谢相关的基因发生变化,并与临床慢性乙肝患者表现相符。研究中有关CypA的发现提供了抑制HBsAg的新途径;有关代谢的变化提出了改变饮食内容与习惯可能有利于HBsAg 阳性感染者的预后。
关键词:乙肝病毒;表面抗原;致病机制;慢性感染
 
New pathogenesis of persistent hepatitis B surface antigen expression
ZHAO Chao, TIAN Xiao-chen, WEN Yu-mei*
Key Laboratory of Medical Molecular Virology, Ministry of Education/ Ministry of Health, Shanghai Medical College, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
Abstract: Persistence of hepatitis B surface antigen (HBsAg) is an important but difficult problem for the control of viral hepatitis B. The aim of this study was to reveal the pathogenesis of HBsAg in hosts, and to provide clues for development of new strategies for inhibition or clearance of HBsAg. Transcriptomic and proteomic technologies were employed together with biological and molecular biological technologies to explore the pathogenesis of hepatitis B surface antigen (HBsAg). In a model of HBsAg positive transgenic mice and HBsAg expressing cell lines, compared to their control counterparts, several new pathogenic mechanisms were observed. The major findings are: (1) HBsAg induced extracellular secretion of cyclophilin A (CypA), which was associated with inflammatory responses in transgenic mice; (2) Proteomic results suggested that HBsAg played a pro-apoptotic role through down-regulation of GRP78; (3) HBsAg induced marked up-regulation of the truncated isoform of lymphoid enhancer-binding factor 1(LEF-1) in cells, which was unable to enhance tumorigenesis and proliferative competence in nude mice; (4) LEF-1 was found with higher incidence to localize in the nucleus in HBV related HCC tissues and was speculated that HBsAg could stimulate proliferation and functional modification of hepatocytes via LEF-1 through the Wnt pathway at the pre-malignant stage; (5) Alterations in carbohydrate, lipid and amino acid metabolism were induced by expression of HBsAg. The new finding of induced secretion of CypA by HBsAg provides new target for inhibition of HBsAg; while the metabolic changes caused by HBsAg expression suggest that by adjusting food habit and nutrition could benefit HBsAg positive hosts by progressing to more favorable prognosis.
Key words: hepatitis B virus; surface antigen; pathogenesis; chronic infection
 
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