title: Activating CAR and β-catenin induces uncontrolled liver growth and tumorigenesis.
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.
authors: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors: Bingning
authors: B
authors: Dong
authors: Department of Systems Biology, MD Anderson Cancer Center, The University of Texas, Houston, Texas 77054, USA.
authors: Ju-Seog
authors: JS
authors: Lee
authors: ASAN Institute for Life Sciences, ASAN Medical Center, Department of Medicine, University of Ulsan College of Medicine, Seoul 138-736, Korea.
authors: Yun-Yong
authors: YY
authors: Park
authors: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors: Feng
authors: F
authors: Yang
authors: Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, California 91010, USA.
authors: Ganyu
authors: G
authors: Xu
authors: Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, California 91010, USA.
authors: Wendong
authors: W
authors: Huang
authors: Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors: Milton J
authors: MJ
authors: Finegold
authors: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors: David D
authors: DD
authors: Moore
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology*; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D016922:Cellular Senescence; D000090702:Constitutive Androstane Receptor; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008099:Liver / Q000254:growth & development* / Q000473:pathology*; D008113:Liver Neoplasms / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000090702:Constitutive Androstane Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin