Activation of the canonical Wnt/β-catenin pathway confers growth advantages in c-Myc/E2F1 transgenic mouse model of liver cancer
Activation of the canonical Wnt/β-catenin pathway confers growth advantages in c-Myc/E2F1 transgenic mouse model of liver cancer
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DOI：
10.1016/j.jhep.2005.01.029
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发表时间：
2005-06-01
影响因子：
25.7
通讯作者：
Thorgeirsson, SS
中科院分区：
文献类型：
--
作者：
Calvisi, DF;Conner, EA;Thorgeirsson, SS
背景/目的：之前，我们发现β -catenin/Wnt通路的激活是c-Myc/E2F1肝癌发生过程中的主要事件。大多数c-Myc/E2F1 hcc在没有β -catenin突变的情况下显示出β -catenin的核积累，这表明Wnt通路其他成员的改变可能是β -catenin核定位的原因。在这里，我们研究了野生型β -连环蛋白核易位的机制，并探讨了Wnt通路在c-Myc/E2F1肝癌发生中的潜在作用。方法：通过微卫星和Western blot分析确定Wnt通路成员的状态。结果：无论是否存在β -连环蛋白突变，大多数c-Myc/E2F1 hcc均表现出Wnt通路的多重异常。观察到的异常包括Wnt-1、卷曲1和2受体、disheveled -1过表达、分泌卷曲相关蛋白-1下调、GSK-3 β失活、轴蛋白位点微卫星不稳定以及β -连环蛋白靶基因如谷氨酰胺合成酶、谷氨酸转运蛋白-1和Wisp-1的诱导。与β -catenin阴性肿瘤相比，β -catenin激活的hcc增殖率更高，肿瘤体积更大。结论：数据表明，Wnt通路成员的多重异常导致β -连环蛋白的核积累，并提示Wnt通路的激活在c-Myc/ e2f1驱动的肝癌发生中具有增殖优势。由爱思唯尔B.V.代表欧洲肝脏研究协会出版。
Background/Aims: Previously, we showed that activation of the beta-catenin/Wnt pathway is a dominant event during c-Myc/E2F1 hepatocarcinogenesis. Majority of c-Myc/E2F1 HCCs displayed nuclear accumulation of beta-catenin in the absence of beta-catenin mutations, suggesting that alterations in other members of the Wnt pathway might be responsible for nuclear localization of beta-catenin. Here, we investigated the mechanisms responsible for nuclear translocation of wild-type beta-catenin and addressed the potential contribution of the Wnt pathway in c-Myc/E2F1 hepatocarcinogenesis.Methods: Status of the members of the Wnt pathway was determined through microsatellite and Western blot analysis.Results: Majority of c-Myc/E2F1 HCCs exhibited multiple abnormalities in the Wnt pathway regardless of the presence of beta-catenin mutations. The observed abnormalities included overexpression of Wnt-1, Frizzled 1 and 2 receptors, Dishevelled-1, downregulation of Secreted frizzled-related protein-1, GSK-3 beta inactivation, microsatellite instability at the Axin locus as well as induction of beta-catenin target genes, such as glutamine synthetase, glutamate transporter-1, and Wisp-1. HCCs with beta-catenin activation displayed significantly higher proliferation rate and larger tumor size when compared with beta-catenin negative tumors.Conclusions: The data demonstrate that multiple abnormalities in the members of the Wnt pathway lead to nuclear accumulation of beta-catenin and suggest that activation of Wnt pathway provides proliferative advantages in c-Myc/E2F1-driven hepatocarcinogenesis. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.