Hepatitis C virus core protein exerts an inhibitory effect on suppressor. of cytokine signaling (SOCS)-1 gene expression
Hepatitis C virus core protein exerts an inhibitory effect on suppressor. of cytokine signaling (SOCS)-1 gene expression
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DOI：
10.1016/j.jhep.2005.03.028
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发表时间：
2005-11-01
影响因子：
25.7
通讯作者：
Koike, K
中科院分区：
文献类型：
--
作者：
Miyoshi, H;Fujie, H;Koike, K
背景/目的：细胞因子信号转导途径的负反馈调节因子SOCS-1也具有肿瘤抑制活性，其基因高甲基化沉默被认为与肝癌的发生有关。目的：探讨丙型肝炎病毒核心蛋白对SOCS-1基因表达的影响。方法：对晚期发生肝细胞癌的丙型肝炎病毒核心基因转基因小鼠、表达核心蛋白的HepG2细胞和人肝组织进行分析。结果：表达核心蛋白的转基因小鼠和表达核心蛋白的HepG2细胞中SOCS-1基因的表达明显受到抑制，而SOCS-3基因的表达被保守。在丙型肝炎病毒阳性的人肝组织中，SOCS-1的表达水平也降低了。在IL-6刺激后，核心蛋白下调信号转导和转录激活因子(STAT)靶基因的表达，而增强STAT1和STAT3的激活。结论：丙型肝炎病毒核心蛋白下调SOCS-1基因的表达。这是一种导致SOCS-1沉默的机制，是该基因高甲基化的替代方案；核心蛋白的这种作用可能调节细胞内信号通路，有助于丙型肝炎病毒感染的发病机制，包括肝癌的发生。(C)2005年欧洲肝脏研究协会。爱思唯尔出版，版权所有。
Background/Aims: Suppressor of cytokine signaling (SOCS)-1, a negative feedback regulator of cytokine signaling pathway, also has a tumor suppressor activity, the silencing of its gene by hypermethylation is suggested to contribute to hepatocarcinogenesis. We studied the effect of the core protein of hepatitis C virus (HCV) on the expression of SOCS-1 gene.Methods: HCV core gene transgenic mice, which develop hepatocellular carcinoma late in life, HepG2 cells expressing the core protein, and human liver tissues were analyzed.Results: The expression of SOCS-1 gene was significantly suppressed in the liver of core gene transgenic mice and HepG2 cells expressing the core protein, while that of SOCS-3 gene was conserved. SOCS-1 expression levels also decreased in HCV-positive human liver tissues. The core protein differentially down-regulated the expression of signal transducer and activator of transcription (STAT) target genes, but rather enhanced STAT1 and STAT3 activation after interleukin-6 stimulation in mouse liver tissues and cells.Conclusions: HCV core protein down-regulates the expression of SOCS-1 gene. This is a mechanism leading to SOCS-1 silencing, an alternative to the hypermethylation of the gene; this effect of the core protein may modulate the intracellular signaling pathway, contributing to the pathogenesis in HCV infection including hepatocarcinogenesis. (c) 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.