Epidermal growth factor receptor:: A novel target of the Wnt/β-catenin pathway in liver
Epidermal growth factor receptor:: A novel target of the Wnt/β-catenin pathway in liver
复制标题
DOI：
10.1053/j.gastro.2005.04.013
复制
发表时间：
2005-07-01
期刊：
影响因子：
29.4
通讯作者：
Monga, SPS
中科院分区：
文献类型：
--
作者：
Tan, XP;Apte, U;Monga, SPS
背景和目的：在正常肝脏发育、再生和肝癌中观察到 Wnt/β-连环蛋白激活。我们的目的是阐明肝脏中该途径的调节和机制。方法：我们报告了肝脏特异性非突变β-连环蛋白过表达转基因小鼠的产生和表征。通过组织学、增殖、凋亡和微阵列分析检查转基因肝脏的形态和表型。结果：与仅表现出主要膜定位的野生型同窝小鼠相比，转基因肝脏显示出肝细胞中细胞质、膜和核β-连环蛋白的显着增加。由于肝细胞增殖增加，转基因小鼠的肝脏重量与体重比明显增加了 15%-20%。微阵列分析显示转基因肝脏中大约 400 个基因的差异表达。在转基因肝脏中观察到表皮生长因子受体 RNA 和蛋白质以及活化的表皮生长因子受体和 Stat3 水平增加。表皮生长因子受体启动子分析显示了 T 细胞因子结合位点，随后的报告分析证实了表皮生长因子受体对 Wnt-3A 治疗的反应，该激活被卷曲相关蛋白 :1（一种已知的 Writ 拮抗剂）所消除。表皮生长因子受体抑制成功地减小了转基因小鼠的肝脏大小。接下来，10 个肝母细胞瘤中有 7 个同时表现出 P-连环蛋白和表皮生长因子受体上调，从而表明肿瘤中这两种蛋白之间存在密切关系。结论：P-连环蛋白转基因小鼠表现出继发于基础肝细胞增殖增加的体内保肝作用。表皮生长因子受体似乎是该途径的直接目标，表皮生长因子受体激活可能有助于肝脏中增加的 P-连环蛋白的一些促有丝分裂作用：表皮生长因子受体抑制可能在这种状态下有用。
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 Writ antagonist. Epidermal growth factor receptor inhibition successfully decreased liver size in transgenic mice. Next, 7 of 10 hepatoblastomas displayed simultaneous P-catenin and epidermal growth factor receptor up-regulation, thus suggesting a strong relationship between these 2 proteins in tumors. Conclusions: P-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 P-catenin in liver: epidermal growth factor receptor inhibition might be useful in such states.