Multiple adaptive mechanisms to chronic liver disease revealed at early stages of liver carcinogenesis in the Mdr2-knockout mice
Multiple adaptive mechanisms to chronic liver disease revealed at early stages of liver carcinogenesis in the Mdr2-knockout mice
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DOI：
10.1158/0008-5472.can-05-2937
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发表时间：
2006-04-15
期刊：
影响因子：
11.2
通讯作者：
Goldenberg, D
中科院分区：
文献类型：
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作者：
Katzenellenbogen, M;Pappo, O;Goldenberg, D
在Mdr2基因敲除（Mdr2-KO）小鼠中研究了肝细胞癌发生前的分子事件。这些小鼠缺乏负责磷脂酰胆碱跨小管膜转运的肝脏特异性P-糖蛋白。门静脉炎在早期发病，1岁后发生肝细胞癌。对处于早期和晚期肝癌前阶段的Mdr2-KO小鼠的肝组织样本进行组织学、生物化学和基因表达谱分析。在早期阶段，发现了多种保护机制，包括诱导许多抗氧化和抗氧化基因，增加肝组织的总抗氧化能力。尽管肝细胞DNA复制的刺激，他们的有丝分裂活动被阻止在这个阶段。在疾病晚期，尽管Mdr2-KO小鼠肝组织的总抗氧化能力正常，炎症也不那么突出，但许多保护性基因仍然过表达。肝细胞有丝分裂活性增加导致多个发育不良结节，其中一些是脂肪变性的。许多调节脂质和磷脂代谢的基因的表达被扭曲，包括胆碱激酶A（一种已知的致癌基因）的上调。许多其他癌基因，包括细胞周期蛋白D1，Jun和一些Ras同源物，在肝脏疾病的两个阶段的Mdr2-KO小鼠中被尖端调控。然而，我们没有发现Ras激活的增加。我们的数据表明，在肝脏疾病的早期阶段诱导的一些适应性机制，保护肝脏免受损伤，可能会在该肝细胞癌模型中的疾病的后期阶段对肝癌发生产生影响。
Molecular events preceding the development of hepatocellular carcinoma were studied in the Mdr2-knockout (Mdr2-KO) mice. These mice lack the liver-specific P-glycoprotein responsible for phosphatidylcholine transport across the canalicular membrane. Portal inflammation ensues at an early age followed by hepatocellular carcinoma development after the age of I year. Liver tissue samples of Mdr2-KO mice in the early and late precancerous stages of liver disease were subjected to histologic, biochemical, and gene expression profiling analysis. In an early stage, multiple protective mechanisms were found, including induction of many antiinflammatory and antioxidant genes and increase of total antioxidant capacity of liver tissue. Despite stimulation of hepatocyte DNA replication, their mitotic activity was blocked at this stage. In the late stage of the disease, although the total antioxidant capacity of liver tissue of Mdr2-KO mice was normal, and inflammation was less prominent, many protective genes remained overexpressed. Increased mitotic activity of hepatocytes resulted in multiple dysplastic nodules, some of them being steatotic. Expression of many genes regulating lipid and phospholipid metabolism was distorted, including up-regulation of choline kinase A, a known oncogene. Many other oncogenes, including cyclin D1, Jun, and some Ras tiontologues, were tip-regulated in Mdr2-KO mice at both stages of liver disease. However, we found no increase of Ras activation. Our data suggest that some of the adaptive mechanisms induced in the early stages of hepatic disease, which protect the liver from injury, could have an effect in hepatocarcinogenesis at later stages of the disease in this hepatocellular carcinoma model.