Increased Activation of the Wnt/β-Catenin Pathway in Spontaneous Hepatocellular Carcinoma Observed in Farnesoid X Receptor Knockout Mice
- 23 March 2011
- journal article
- research article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Journal of Pharmacology and Experimental Therapeutics
- Vol. 338 (1), 12-21
- https://doi.org/10.1124/jpet.111.179390
Abstract
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/β-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 β-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. β-Catenin activation further increased significantly in 14-month-old tumor-bearing mice. Further analysis revealed that two independent mechanisms might be involved in β-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-3β inactivation. We also observed decreased expression of E-cadherin, a known regulator of β-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/β-catenin is observed during spontaneous HCC development in FXR-KO mice and is potentially critical for tumor development.Keywords
This publication has 48 references indexed in Scilit:
- Convergence between Wnt-β-catenin and EGFR signaling in cancerMolecular Cancer, 2010
- Upregulation of early growth response factor-1 by bile acids requires mitogen-activated protein kinase signalingToxicology and Applied Pharmacology, 2010
- Beta-Catenin Activation Promotes Liver Regeneration after Acetaminophen-Induced InjuryThe American Journal of Pathology, 2009
- Bile acids as regulatory moleculesJournal of Lipid Research, 2009
- Cadherins and cancer: how does cadherin dysfunction promote tumor progression?Oncogene, 2008
- Farnesoid X Receptor Deficiency in Mice Leads to Increased Intestinal Epithelial Cell Proliferation and Tumor DevelopmentJournal of Pharmacology and Experimental Therapeutics, 2008
- Molecular mechanisms of hepatocellular carcinomaHepatology, 2008
- Molecular targeted therapies in hepatocellular carcinomaHepatology, 2008
- Spontaneous hepatocarcinogenesis in farnesoid X receptor-null miceCarcinogenesis: Integrative Cancer Research, 2006
- The transcription factor Snail is a repressor of E-cadherin gene expression in epithelial tumour cellsNature, 2000