Marshall Aileen, Rushbrook Simon, Davies Susan E, Morris Lesley S, Scott Ian S, Vowler Sarah L, Coleman Nicholas, Alexander Graeme
Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Hills Road, Cambridge CB2 2QQ, England, UK.
Gastroenterology. 2005 Jan;128(1):33-42. doi: 10.1053/j.gastro.2004.09.076.
BACKGROUNDS & AIMS: An increased risk of hepatitis C virus (HCV)-related cirrhosis is associated with hepatic steatosis, older age, and high alcohol consumption, which could be explained by synergistic effects on cell proliferation. We aimed to investigate hepatocyte cell cycle state and phase distribution in chronic HCV infection.
Liver biopsy specimens diagnostic for chronic HCV (70), liver regeneration following transplant-related ischemic-reperfusion injury (15), and "normal" liver adjacent to colorectal cancer metastasis (10) were studied. Immunohistochemistry was used to detect cell cycle phase markers cyclin D1 (maximal in G 1 ), cyclin A (S), cyclin B1 (cytoplasmic during G 2 ) and phosphorylated histone 3 protein (mitosis), mini-chromosome maintenance protein 2 (Mcm-2; present throughout the cell cycle), and cyclin-dependent kinase inhibitor p21, which inhibits G 1 /S progression.
Hepatocyte Mcm-2 expression was elevated in chronic HCV and liver regeneration (13% vs 26.4%) but negligible in "normal" liver. In proportion to Mcm-2, there was no difference in cyclin D1 between chronic HCV infection and liver regeneration (51.6% of Mcm-2-positive hepatocytes vs 52.6%). In contrast, there was a striking reduction in cyclin A (3% vs 16.3%), cyclin B1 (.4% vs 2.3%), and phosphorylated histone 3 protein (0% vs 3.8%) in chronic HCV infection compared with liver regeneration. In chronic HCV infection, Mcm-2 and p21 expression were associated with fibrosis stage and positive serum HCV RNA.
The data are consistent with hepatocyte G 1 arrest in chronic HCV infection. This could impair hepatocellular function and limit hepatic regeneration.
丙型肝炎病毒（HCV）相关肝硬化风险增加与肝脂肪变性、老年及高酒精摄入量有关，这可能是对细胞增殖的协同作用所致。我们旨在研究慢性HCV感染时肝细胞的细胞周期状态和阶段分布。
研究了诊断为慢性HCV的肝活检标本（70例）、移植相关缺血再灌注损伤后的肝再生标本（15例）以及结直肠癌转移灶旁的“正常”肝脏标本（10例）。采用免疫组织化学检测细胞周期阶段标志物细胞周期蛋白D1（在G1期达峰值）、细胞周期蛋白A（S期）、细胞周期蛋白B1（G2期位于细胞质）和磷酸化组蛋白3蛋白（有丝分裂期）、微小染色体维持蛋白2（Mcm-2；在整个细胞周期均存在）以及抑制G1/S期进展的细胞周期蛋白依赖性激酶抑制剂p21。
慢性HCV和肝再生时肝细胞Mcm-2表达升高（分别为13%和26.4%），而在“正常”肝脏中可忽略不计。与Mcm-2成比例，慢性HCV感染和肝再生时细胞周期蛋白D1无差异（Mcm-2阳性肝细胞分别为51.6%和52.6%）。相反，与肝再生相比，慢性HCV感染时细胞周期蛋白A（3%对16.3%）、细胞周期蛋白B1（0.4%对2.3%）和磷酸化组蛋白3蛋白（0%对3.8%）显著减少。在慢性HCV感染中，Mcm-2和p21表达与纤维化分期及血清HCV RNA阳性相关。
数据表明慢性HCV感染时肝细胞处于G1期阻滞状态。这可能损害肝细胞功能并限制肝脏再生。
