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Carcinogenesis Advance Access originally published online on December 20, 2006
Carcinogenesis 2007 28(5):940-946; doi:10.1093/carcin/bgl249
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Published by Oxford University Press 2006.

Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice

Insook Kim, Keiichirou Morimura, Yatrik Shah, Qian Yang, Jerrold M. Ward and Frank J. Gonzalez*

Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA

* To whom correspondence should be addressed. Tel: +301 496 9067; Fax: +301 496 8409; Email: fjgonz{at}helix.nih.gov

The farnesoid X receptor (FXR) controls the synthesis and transport of bile acids (BAs). Mice lacking expression of FXR, designated Fxr-null, have elevated levels of serum and hepatic BAs and an increase in BA pool size. Surprisingly, at 12 months of age, male and female Fxr-null mice had a high incidence of degenerative hepatic lesions, altered cell foci and liver tumors including hepatocellular adenoma, carcinoma and hepatocholangiocellular carcinoma, the latter of which is rarely observed in mice. At 3 months, Fxr-null mice had increased expression of the proinflammatory cytokine IL-1ß mRNA and elevated ß-catenin and its target gene c-myc. They also had increased cell proliferation as revealed by increased PCNA mRNA and BrdU incorporation. These studies reveal a potential role for FXR and BAs in hepatocarcinogenesis.

Abbreviations: BA, bile acid; FXR, farnesoid X receptor; HCC, hepatocellular carcinoma; HSC, hepatic stellate cell; PBS, phosphate-buffered saline; qPCR, quantitative polymerase chain reaction; RT, room temperature; WT, wild-type

Received August 25, 2006; revised November 27, 2006; accepted December 7, 2006.


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