Zonal gene expression in mouse liver resembles expression patterns of Ha-ras and β-catenin mutated hepatomas
Zonal gene expression in mouse liver resembles expression patterns of Ha-ras and β-catenin mutated hepatomas
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DOI：
10.1124/dmd.106.013656
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发表时间：
2007-04-01
影响因子：
3.9
通讯作者：
Schwarz, Michael
中科院分区：
文献类型：
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作者：
Braeuning, Albert;Ittrich, Carina;Schwarz, Michael
肝小叶的门静脉周围区和静脉周围区的肝细胞在各种酶和其他蛋白质的水平和活性上存在差异。我们最近提出，依赖于β-连环蛋白和RAS的信号通路在静脉周围和门静脉周围基因表达谱的调节中起着重要作用。这一假说主要是基于正常肝细胞基因表达的地带性差异与肝肿瘤基因表达模式的相似性：在Ha-ras突变的小鼠肝肿瘤中，几种优先在门静脉周围肝细胞中优先表达的蛋白质和mRNAs经常过表达，而在CTNNB1(编码β-连环蛋白)突变的肿瘤中，静脉周围标志物过表达。我们现在通过使用之前进行的两个微阵列分析的数据扩展了这项工作，这些分析旨在分析1)Ha-ras和CTNNB1突变小鼠肝肿瘤的全球基因表达模式，以及2)门静脉周围和静脉周围小鼠肝细胞之间的转录组差异。通过对数据集的比较，鉴定出在两个数据集中都存在的134个基因或表达序列。静脉周围肝细胞和CTNNB1突变的肝癌细胞中的基因表达模式具有很强的相关性：两个数据集中96.5%的基因是同一方向调控的。类似地，在Ha-ras突变的肿瘤中，74.1%的非调控基因的表达与各自在门静脉周围肝细胞中的表达模式相关。这些发现支持这样一种假设，即门静脉周围和静脉周围肝细胞中的基因表达模式至少部分受到RAS和β-连环蛋白依赖的信号通路的调节。
Hepatocytes of the periportal and perivenous zones of the liver lobule differ in their levels and activities of various enzymes and other proteins. We have recently suggested that beta-catenin- and Ras-dependent signaling pathways play an important role in the regulation of perivenous and periportal gene expression profiles. This hypothesis was primarily based on similarities in zonal differences in gene expression of hepatocytes from normal liver with gene expression patterns of liver tumors: several proteins and mRNAs preferentially expressed in periportal hepatocytes were often overexpressed in Ha-ras mutated mouse liver tumors, whereas perivenous markers were overexpressed in Ctnnb1 ( encoding beta-catenin) mutated tumors. We have now extended this work by use of data from two previously conducted microarray analyses aimed to analyze 1) global gene expression patterns of Ha-ras and Ctnnb1 mutated mouse liver tumors and 2) transcriptome differences between periportal and perivenous mouse hepatocytes. By comparison of the datasets, 134 genes or expressed sequences were identified that were present in both datasets. Gene expression patterns in perivenous hepatocytes and Ctnnb1 mutated hepatoma cells were strongly correlated: 96.5% of the genes present in both datasets were regulated in the same direction. In analogy, expression of 74.1% of the genes deregulated in Ha-ras mutated tumors was correlated with the respective expression patterns in periportal hepatocytes. These findings favor the hypothesis that gene expression patterns in periportal and perivenous hepatocytes are regulated, at least in part, by Ras- and beta-catenin-dependent signaling pathways.