The Hepatitis B Virus X Protein Modulates Hepatocyte Proliferation Pathways To Stimulate Viral Replication
The Hepatitis B Virus X Protein Modulates Hepatocyte Proliferation Pathways To Stimulate Viral Replication
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DOI：
10.1128/jvi.02196-09
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发表时间：
2010-03-01
影响因子：
5.4
通讯作者：
Bouchard, Michael J.
中科院分区：
文献类型：
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作者：
Gearhart, Tricia L.;Bouchard, Michael J.
在世界范围内，有超过3.5亿人慢性感染人类B型肝炎病毒（HBV）;慢性HBV感染与肝细胞癌（HCC）的发展相关。各种研究结果表明，HBV X蛋白（HBx）在HBV相关性HCC的发展中起作用。HBx可以调节许多细胞信号转导途径，包括那些调节细胞增殖的途径。许多以前的研究分析了HBx对细胞增殖途径的影响，使用已建立的或永生化的细胞系进行，当HBx在HBV复制的情况下表达时，HBx对这些途径的确切影响往往取决于实验条件。我们研究了HBx对培养的原代大鼠肝细胞（一个生物学相关系统）细胞增殖的影响。我们证明，HBx本身和HBV复制的背景下，影响各种细胞周期调节蛋白的水平和活性，诱导正常静止的肝细胞进入细胞周期的G（1）期，但不进行S期。我们将HBx对细胞增殖的调节与细胞溶质钙信号传导和HBx对HBV复制的刺激联系起来。我们的研究表明，HBx诱导正常静止的肝细胞进入细胞周期的G（1）期，这种钙依赖性HBx活性是HBV复制所必需的。这些研究确定了HBx在HBV复制过程中的重要功能，以及可能将HBV感染与HCC发展联系起来的机制。
Worldwide, there are over 350 million people who are chronically infected with the human hepatitis B virus (HBV); chronic HBV infections are associated with the development of hepatocellular carcinoma (HCC). The results of various studies suggest that the HBV X protein (HBx) has a role in the development of HBV-associated HCC. HBx can regulate numerous cellular signal transduction pathways, including those that modulate cell proliferation. Many previous studies that analyzed the impact of HBx on cell proliferation pathways were conducted using established or immortalized cell lines, and when HBx was expressed in the absence of HBV replication, and the precise effect of HBx on these pathways has often differed depending on experimental conditions. We have studied the effect of HBx on cell proliferation in cultured primary rat hepatocytes, a biologically relevant system. We demonstrate that HBx, both by itself and in the context of HBV replication, affected the levels and activities of various cell cycle-regulatory proteins to induce normally quiescent hepatocytes to enter the G(1) phase of the cell cycle but not to proceed to S phase. We linked HBx regulation of cell proliferation to cytosolic calcium signaling and HBx stimulation of HBV replication. Cumulatively, our studies suggest that HBx induces normally quiescent hepatocytes to enter the G(1) phase of the cell cycle and that this calcium-dependent HBx activity is required for HBV replication. These studies identify an essential function of HBx during HBV replication and a mechanism that may connect HBV infections to the development of HCC.