丙型肝炎病毒和酒精：相同的有丝分裂靶点，但不同的信号通路。

Hepatitis C virus and alcohol: same mitotic targets but different signaling pathways.

机构信息

Laboratory of Molecular Virology and Oncology, Fondazione A. Cesalpino, University of Rome, Rome, V. le del Policlinico 155, 00161 Rome, Italy.

出版信息

J Hepatol. 2011 May;54(5):956-63. doi: 10.1016/j.jhep.2010.08.016. Epub 2010 Dec 22.

DOI:10.1016/j.jhep.2010.08.016

PMID:21145809

Abstract

BACKGROUND & AIMS: Chromosomal aberrations are frequently observed in hepatitis C virus (HCV)- and alcohol-related hepatocellular carcinomas (HCCs). The mechanisms by which chromosomal aberrations occur during hepatocarcinogenesis are still unknown. However, these aberrations are considered to be the result of deregulation of some mitotic proteins, including the alteration of Cyclin B1 and Aurora kinase A expression, and the phosphorylation of gamma-tubulin. Our study aims at investigating changes in expression of the above mentioned proteins and related intracellular pathways, in in vitro and in vivo models of both HCV- and alcohol- dependent HCCs.

METHODS

In this study, the molecular defects and the mechanisms involved in deregulation of the mitotic machinery were analyzed in human hepatoma cells, expressing HCV proteins treated or not with ethanol, and in liver tissues from control subjects (n=10) and patients with HCV- (n=10) or alcohol-related (n=10) HCCs.

RESULTS

Expression of Cyclin B1, Aurora kinase A, and tyrosine-phosphorylated gamma-tubulin was analyzed in models reproducing HCV infection and ethanol treatment in HCC cells. Interestingly, HCV and alcohol increased the expression of Cyclin B, Aurora kinase A, and tyrosine-phosphorylated gamma-tubulin also in tissues from patients with HCV- or alcohol-related HCCs. In vitro models suggest that HCV requires the expression of PKR (RNA-activated protein kinase), as well as JNK (c-Jun N-terminal kinase) and p38MAPK (p38 mitogen-activated protein kinase) proteins; while, ethanol bypasses all these pathways.

CONCLUSIONS

Our results support the idea that HCV and alcohol may promote oncogenesis by acting through the same mitotic proteins, but via different signaling pathways.

摘要

背景与目的

染色体异常在丙型肝炎病毒（HCV）和酒精相关的肝细胞癌（HCC）中经常观察到。在肝癌发生过程中染色体异常发生的机制尚不清楚。然而，这些异常被认为是一些有丝分裂蛋白失调的结果，包括细胞周期蛋白 B1 和 Aurora 激酶 A 表达的改变，以及γ-微管蛋白的磷酸化。我们的研究旨在研究 HCV 和酒精依赖 HCC 的体外和体内模型中上述蛋白的表达变化及相关的细胞内途径。

方法

在这项研究中，分析了表达 HCV 蛋白的人肝癌细胞中，有丝分裂机制失调的分子缺陷和机制，这些细胞经或未经乙醇处理，并分析了来自对照组（n=10）和丙型肝炎病毒（n=10）或酒精相关（n=10）HCC 患者的肝组织中的相关机制。

结果

在模拟 HCV 感染和 HCC 细胞乙醇处理的模型中，分析了细胞周期蛋白 B1、Aurora 激酶 A 和酪氨酸磷酸化γ-微管蛋白的表达。有趣的是，HCV 和酒精也增加了丙型肝炎病毒或酒精相关 HCC 患者肝组织中 Cyclin B、Aurora 激酶 A 和酪氨酸磷酸化γ-微管蛋白的表达。体外模型表明，HCV 需要 PKR（RNA 激活蛋白激酶）以及 JNK（c-Jun N-末端激酶）和 p38MAPK（p38 丝裂原激活蛋白激酶）蛋白的表达；而乙醇则绕过了所有这些途径。