Insights into the pathobiology of hepatitis C virus-associated cirrhosis - Analysis of intrahepatic differential gene expression
Insights into the pathobiology of hepatitis C virus-associated cirrhosis - Analysis of intrahepatic differential gene expression
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DOI：
10.1016/s0002-9440(10)64884-5
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发表时间：
2002-02-01
影响因子：
6
通讯作者：
McCaughan, GW
中科院分区：
文献类型：
--
作者：
Shackel, NA;McGuinness, PH;McCaughan, GW
丙型肝炎病毒（HCV）相关性肝损伤的发病机制涉及多个致病途径的多个基因。cDNA阵列分析，同时检查许多基因的表达，被用来实现新的见解丙型肝炎病毒肝损伤。874个基因的基于膜的cDNA阵列比较了HCV相关性肝硬化与自身免疫性肝炎相关性肝硬化作为炎症和炎症对照，以及与非病变肝组织。阵列分析鉴定了许多在炎症、纤维化、增殖、信号传导、凋亡和氧化应激中重要的差异表达基因。HCV相关肝硬化中上调的基因主要与Th 1免疫应答、纤维化、细胞增殖和凋亡相关。差异基因表达的新观察结果包括分泌型凋亡相关蛋白3（一种可能参与细胞凋亡的Wnt途径基因）的表达增加。EMMPRIN（CD 147）和盘状结构域受体1（CD-167）也显示增加，并可能在肝纤维化中发挥作用。实时定量逆转录-聚合酶链反应证实了15个基因的表达增加。HCV肝硬化与自身免疫性肝炎肝硬化的比较显示，HCV肝硬化的特征是促凋亡基因表达增加，而自身免疫性肝炎的特征是抗凋亡和促凋亡基因表达增加，在凋亡相关基因谱中存在显著差异。此外，P-连环蛋白和纤维化相关蛋白EMMPRIN的表达通过免疫组织化学定位于肝细胞和胆管上皮的质膜。总之，HCV相关性肝硬化的特征在于促炎、促纤维化和促凋亡基因表达谱。
The pathogenesis of hepatitis C virus (HCV)-associated liver injury involves many genes from multiple pathogenic pathways. cDNA array analysis, which examines the expression of many genes simultaneously, was used to achieve new insights into HCV liver injury. Membrane-based cDNA arrays of 874 genes compared HCV-associated cirrhosis with autoimmune hepatitis-associated cirrhosis as an inflammatory and cirrhotic control, and with nondiseased liver tissue. Array analysis identified many differentially expressed genes that are important in inflammation, fibrosis, proliferation, signaling, apoptosis, and oxidative stress. Genes up-regulated in HCV-associated cirrhosis were predominantly associated with a Th1 immune response, fibrosis, cellular proliferation, and apoptosis. Novel observations of differential gene expression included increased expression of secreted apoptosis-related protein 3, a Wnt pathway gene possibly involved in cellular apoptosis. EMMPRIN (CD147) and discoidin domain receptor 1 (CD-167) were also shown to be increased and are likely to play a role in liver fibrosis. Real-time quantitative reverse transcriptase-polymerase chain reaction confirmed the increased expression of 15 genes. The comparison of HCV cirrhosis with autoimmune hepatitis cirrhosis showed a marked difference in the apoptosis-associated gene profile with HCV cirrhosis characterized by increased proapoptotic gene expression whereas autoimmune hepatitis was characterized by increased expression of both antiapoptotic and proapoptotic genes. Furthermore, expression of P-catenin and the fibrosis-associated protein EMMPRIN were localized by immunohistochemistry to the plasma membranes of hepatocytes and biliary epithelium. in conclusion, HCV-associated cirrhosis was characterized by a proinflammatory, profibrotic, and proapoptotic gene expression profile.