表皮生长因子受体：肝脏中Wnt/β-连环蛋白信号通路的新靶点。
Epidermal growth factor receptor: a novel target of the Wnt/beta-catenin pathway in liver.
作者信息
Tan Xinping, Apte Udayan, Micsenyi Amanda, Kotsagrelos Emorphia, Luo Jian-Hua, Ranganathan Sarangarajan, Monga Dulabh K, Bell Aaron, Michalopoulos George K, Monga Satdarshan P S
机构信息
Department of Pathology, University of Pittsburgh, School of Medicine, Pennsylvania 15261, USA.
出版信息
Gastroenterology. 2005 Jul;129(1):285-302. doi: 10.1053/j.gastro.2005.04.013.
BACKGROUND & AIMS: Wnt/beta-catenin activation is observed in normal liver development, regeneration, and liver cancer. Our aim was to elucidate the regulation and mechanism of this pathway in liver.
METHODS
We report the generation and characterization of liver-specific nonmutated beta-catenin-overexpressing transgenic mice. Transgenic livers were examined for their morphology and phenotype by histology, proliferation, apoptosis, and microarray analysis.
RESULTS
Transgenic livers displayed a significant increase in cytoplasmic, membranous, and nuclear beta-catenin in hepatocytes as compared with their wild-type littermates, which display a predominant membranous localization only. A 15%-20% increase in the liver weight-body weight ratio was evident in transgenic mice secondary to increased hepatocyte proliferation. Microarray analysis showed differential expression of approximately 400 genes in the transgenic livers. Epidermal growth factor receptor RNA and protein and increased levels of activated epidermal growth factor receptor and Stat3 were observed in the transgenic livers. Epidermal growth factor receptor promoter analysis showed a T-cell factor-binding site, and subsequent reporter assay confirmed epidermal growth factor receptor activation in response to Wnt-3A treatment that was abrogated by frizzled related protein 1, a known Wnt antagonist. Epidermal growth factor receptor inhibition successfully decreased liver size in transgenic mice. Next, 7 of 10 hepatoblastomas displayed simultaneous beta-catenin and epidermal growth factor receptor up-regulation, thus suggesting a strong relationship between these 2 proteins in tumors.
CONCLUSIONS
beta-Catenin transgenic mice show an in vivo hepatotrophic effect secondary to increased basal hepatocyte proliferation. Epidermal growth factor receptor seems to be a direct target of the pathway, and epidermal growth factor receptor activation might contribute toward some mitogenic effects of increased beta-catenin in liver: epidermal growth factor receptor inhibition might be useful in such states.
背景与目的
在正常肝脏发育、再生及肝癌中均观察到Wnt/β-连环蛋白信号通路的激活。我们的目的是阐明该信号通路在肝脏中的调控及机制。
方法
我们报道了肝脏特异性非突变β-连环蛋白过表达转基因小鼠的构建及特性研究。通过组织学、增殖、凋亡及基因芯片分析，对转基因肝脏的形态和表型进行检测。
结果
与仅呈现主要膜定位的野生型同窝小鼠相比，转基因肝脏中肝细胞的细胞质、膜及细胞核β-连环蛋白显著增加。由于肝细胞增殖增加，转基因小鼠的肝脏重量与体重之比明显增加了15%-20%。基因芯片分析显示转基因肝脏中约400个基因表达存在差异。在转基因肝脏中观察到表皮生长因子受体RNA和蛋白以及活化的表皮生长因子受体和Stat3水平升高。表皮生长因子受体启动子分析显示有一个T细胞因子结合位点，随后的报告基因检测证实，在受到Wnt-3A处理时表皮生长因子受体被激活，而这种激活可被已知的Wnt拮抗剂卷曲相关蛋白1消除。抑制表皮生长因子受体成功减小了转基因小鼠的肝脏大小。接下来，10例肝母细胞瘤中有7例同时出现β-连环蛋白和表皮生长因子受体上调，这表明这两种蛋白在肿瘤中存在密切关系。
结论
β-连环蛋白转基因小鼠因基础肝细胞增殖增加而表现出体内肝营养效应。表皮生长因子受体似乎是该信号通路的直接靶点，表皮生长因子受体激活可能有助于增强肝脏中β-连环蛋白的某些促有丝分裂作用：抑制表皮生长因子受体在这种情况下可能有用。
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