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.
Footnotes
This work was supported by the National Institutes of Health National Center for Research Resources [Grant 1 P20-RR021940-03]; the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant R01-DK031343]; and University of Kansas Endowment Startup Funds.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.111.179390.
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The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- FXR
- farnesoid X receptor
- HCC
- hepatocellular carcinoma
- GSK-3β
- glycogen synthase kinase 3β
- Dvl
- dishevelled
- Fzl
- frizzled
- FXR-KO
- farnesoid X receptor knockout
- SHP
- small heterodimer partner
- BSEP
- bile salt export pump
- PCR
- polymerase chain reaction
- WT
- wild-type
- RIPA
- radioimmunoprecipitation assay.
- Received January 13, 2011.
- Accepted March 23, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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