title: Effect of mutant β-catenin on liver growth homeostasis and hepatocarcinogenesis in transgenic mice.
abstract: BACKGROUND
  Mutations in the Wnt signalling pathway molecule β-catenin are associated with liver cancer.
  
  
  OBJECTIVE
  Our aim was to confirm the effects of stabilized β-catenin on liver growth, identify whether those effects were reversible and cell autonomous or non-cell autonomous and to model β-catenin-induced liver cancer in mice.
  
  
  METHODS
  Using a liver-specific inducible promoter, we generated transgenic mice in which the expression of mutant β-catenin can be induced or repressed within hepatocytes in mice of different ages.
  
  
  RESULTS
  Similar to other models, the hepatic expression of mutant β-catenin in our model beginning in utero or induced in quiescent adult liver resulted in a two-fold liver enlargement and development of disease with a latency of 1-5 months, and mice displayed elevated blood ammonia and altered hepatic gene expression. Our model additionally allowed us to discover that molecular and phenotypic abnormalities were reversible following the inhibition of transgene expression. Hepatocyte transplant studies indicated that mutant β-catenin could not increase the growth of transgene-expressing foci in either growth-permissive or -restrictive hepatic environments, but still directly altered hepatocyte gene expression. Mice with continuous but focal transgene expression developed hepatic neoplasms after the age of 1 year.
  
  
  CONCLUSIONS
  Our findings indicate that hepatocyte gene expression is directly affected by mutant β-catenin in a cell autonomous manner. However, hepatomegaly associated with diffuse hepatocyte-specific expression of mutant β-catenin is secondary to liver functional alteration or non-cell autonomous. Both phenotypes are reversible. Nevertheless, some foci of transgene-expressing cells progressed to carcinoma, confirming the association of mutant β-catenin with liver cancer.
authors.affiliation: Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Stein
authors.forename: Adam
authors.initials: A
authors.lastname: Jochem
authors.forename: Katie E
authors.initials: KE
authors.lastname: Holmes
authors.forename: Eric P
authors.initials: EP
authors.lastname: Sandgren
mesh_terms: D000818:Animals; D017690:Cell Transplantation; D004318:Doxycycline / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D020868:Gene Silencing / Q000187:drug effects; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D006529:Hepatomegaly / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis; D008099:Liver / Q000254:growth & development*; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics* / Q000378:metabolism; D009929:Organ Size / Q000235:genetics; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: C495267:CTNNB1 protein, mouse; D050505:Mutant Proteins; D051176:beta Catenin; D004318:Doxycycline