Increased Activation of the Wnt/β-Catenin Pathway in Spontaneous Hepatocellular Carcinoma Observed in Farnesoid X Receptor Knockout Mice
Increased Activation of the Wnt/β-Catenin Pathway in Spontaneous Hepatocellular Carcinoma Observed in Farnesoid X Receptor Knockout Mice
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DOI：
10.1124/jpet.111.179390
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发表时间：
2011-07-01
影响因子：
3.5
通讯作者：
Apte, Udayan
中科院分区：
文献类型：
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作者：
Wolfe, Andy;Thomas, Ann;Apte, Udayan
法尼醇X受体（FXR）是一种主要的胆汁酸敏感核受体，也以其抗癌特性而闻名。已知小鼠中FXR缺乏导致自发性肝细胞癌（HCC），但其机制尚不完全清楚。我们报道了在FXR基因敲除（KO）小鼠中Wnt/β-连环蛋白通路的持续激活与自发性HCC相关。在3、8和14月龄的FXR-KO小鼠中研究HCC发展。在3个月或8个月时均未观察到肿瘤，但在14个月龄时在100%的FXR-KO小鼠中观察到HCC的存在。进一步的分析显示，在3个月大的FXR-KO小鼠的肝脏中，β-连环蛋白活化没有变化，但在8个月大的FXR-KO小鼠中观察到中度增加。β-连环蛋白活化在14个月大的荷瘤小鼠中进一步显著增加。进一步的分析表明，两个独立的机制可能涉及在FXR-KO小鼠的肝脏中的β-连环蛋白激活。经典Wnt信号传导的激活是明显的，如Wnt 4增加和凌乱表达沿着糖原合成酶激酶-3 β失活所示。我们还观察到FXR-KO小鼠中E-钙粘蛋白（一种已知的β-连环蛋白调节因子）的表达降低。E-钙粘蛋白表达的减少伴随着其转录抑制子Snail表达的增加。与FXR-KO小鼠中HCC增加一致，我们观察到人HCC样品中FXR表达和活性显著降低。总之，这些数据表明，在FXR-KO小鼠中自发性HCC发展期间观察到Wnt/β-连环蛋白活化的时间增加，并且对肿瘤发展可能至关重要。
Farnesoid X receptor (FXR), the primary bile acid-sensing nuclear receptor, also is known for its anticancer properties. It is known that FXR deficiency in mice results in spontaneous hepatocellular carcinoma (HCC), but the mechanisms are not completely understood. We report that sustained activation of the Wnt/beta-catenin pathway is associated with spontaneous HCC in FXR-knockout (KO) mice. HCC development was studied in FXR-KO mice at 3, 8, and 14 months of age. No tumors were observed at either 3 or 8 months, but the presence of HCC was observed in 100% of the FXR-KO mice at the age of 14 months. Further analysis revealed no change in beta-catenin activation in the livers of 3-month-old FXR-KO mice, but a moderate increase was observed in 8-month-old FXR-KO mice. beta-Catenin activation further increased significantly in 14-month-old tumor-bearing mice. Further analysis revealed that two independent mechanisms might be involved in beta-catenin activation in the livers of FXR-KO mice. Activation of canonical Wnt signaling was evident as indicated by increased Wnt4 and dishevelled expression along with glycogen synthase kinase-3 beta inactivation. We also observed decreased expression of E-cadherin, a known regulator of beta-catenin, in FXR-KO mice. The decrease in E-cadherin expression was accompanied by increased expression of its transcriptional repressor, Snail. Consistent with the increased HCC in FXR-KO mice, we observed a significant decrease in FXR expression and activity in human HCC samples. Taken together, these data indicate that a temporal increase in the activation of Wnt/beta-catenin is observed during spontaneous HCC development in FXR-KO mice and is potentially critical for tumor development.