Global increase of p16INK4a in APC-deficient mouse liver drives clonal growth of p16INK4a negative tumors


  • E. Ueberham
  • P. Glöckner
  • C. Göhler
  • B.K. Straub
  • D. Teupser
  • K. Schönig
  • A. Braeuning
  • A.K. Höhn
  • B. Jerchow
  • W. Birchmeier
  • F. Gaunitz
  • T. Arendt
  • O. Sansom
  • R. Gebhardt
  • U. Ueberham


  • Molecular Cancer Research


  • Mol Cancer Res 13 (2): 239-249


  • Reduction of beta-catenin (CTNNB1) destroying complex components, e.g. adenomatous polyposis coli (APC), induces beta-catenin signaling and subsequently triggers activation of genes involved in proliferation and tumorigenesis. Though diminished expression of APC has organ specific and threshold dependent influence on the development of liver tumors in mice, the molecular basis is poorly understood. Therefore, a detailed investigation was conducted to determine the underlying mechanism in the development of liver tumors under reduced APC levels. Mouse liver at different developmental stages was analyzed in terms of beta-catenin target genes including Cyp2e1, Glul and Ihh using real-time RT-PCR, reporter gene assays and immunohistological methods with consideration of liver zonation. Data from human livers with mutations in APC derived from FAP patients were also included. Hepatocyte senescence was investigated by determining p16(INK4a) expression level, presence of senescence-associated beta-galactosidase (SA-beta-Gal) activity and assessing ploidy. A beta-catenin activation of hepatocytes does not always result in beta-catenin positivity but unexpectedly also in mixed and beta-catenin negative tumors. In summary, a senescence inducing program was found in hepatocytes with increased beta-catenin levels and a positive selection of hepatocytes lacking p16(INK4a), by epigenetic silencing, drives the development of liver tumors in mice with reduced APC expression (Apc(580S) mice). The lack of p16(INK4a) was also detected in liver tumors of mice with triggers other than APC reduction. Implications: Epigenetic silencing of p16(Ink4a) in selected liver cells bypassing senescence is a general principle for development of liver tumors with beta-catenin involvement in mice independent of the initial stimulus.