Activating CAR and β-catenin induces uncontrolled liver growth and tumorigenesis

Bingning Dong, Ju-Seog Lee, Yun-Yong Park, Feng Yang, Ganyu Xu, Wendong Huang, Milton J. Finegold and David D. Moore ()
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Bingning Dong: Baylor College of Medicine, One Baylor Plaza
Ju-Seog Lee: MD Anderson Cancer Center, The University of Texas
Yun-Yong Park: ASAN Institute for Life Sciences, ASAN Medical Center, University of Ulsan College of Medicine
Feng Yang: Baylor College of Medicine, One Baylor Plaza
Ganyu Xu: Beckman Research Institute, City of Hope National Medical Center
Wendong Huang: Beckman Research Institute, City of Hope National Medical Center
Milton J. Finegold: Baylor College of Medicine, One Baylor Plaza
David D. Moore: Baylor College of Medicine, One Baylor Plaza

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: Abstract Aberrant β-catenin activation contributes to a third or more of human hepatocellular carcinoma (HCC), but β-catenin activation alone is not sufficient to induce liver cancer in mice. Differentiated hepatocytes proliferate upon acute activation of either β-catenin or the nuclear xenobiotic receptor CAR. These responses are strictly limited and are tightly linked, since β-catenin is activated in nearly all of the CAR-dependent tumours generated by the tumour promoter phenobarbital. Here, we show that full activation of β-catenin in the liver induces senescence and growth arrest, which is overcome by combined CAR activation, resulting in uncontrolled hepatocyte proliferation, hepatomegaly and rapid lethality despite maintenance of normal liver function. Combining CAR activation with limited β-catenin activation induces tumorigenesis, and the tumours share a conserved gene expression signature with β-catenin-positive human HCC. These results reveal an unexpected route for hepatocyte proliferation and define a murine model of hepatocarcinogenesis with direct relevance to human HCC.

Date: 2015
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DOI: 10.1038/ncomms6944

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