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

Abstract

UNLABELLED:

Reduction of β-catenin (CTNNB1) destroying complex components, for example, adenomatous polyposis coli (APC), induces β-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 β-catenin target genes including Cyp2e1, Glul, and Ihh using real-time RT-PCR, reporter gene assays, and immunohistologic methods with consideration of liver zonation. Data from human livers with mutations in APC derived from patients with familial adenomatous polyposis (FAP) were also included. Hepatocyte senescence was investigated by determining p16(INK4a) expression level, presence of senescence-associated β-galactosidase activity, and assessing ploidy. A β-catenin activation of hepatocytes does not always result in β-catenin positive but unexpectedly also in mixed and β-catenin-negative tumors. In summary, a senescence-inducing program was found in hepatocytes with increased β-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 β-catenin involvement in mice independent of the initial stimulus.

• Authors: Elke Ueberham, Pia Glöckner, Claudia Göhler, Beate K Straub, Daniel Teupser, Kai Schönig, Albert Braeuning, Anne Kathrin Höhn, Boris Jerchow, Walter Birchmeier, Frank Gaunitz, Thomas Arendt, Owen Sansom, Rolf Gebhardt, Uwe Ueberham
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 13 Issue 2 Pg. 239-49 (Feb 2015) ISSN: 1557-3125 [Electronic] United States
• PMID: 25270420 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Adenomatous Polyposis Coli Protein
• CTNNB1 protein, mouse
• Cdkn2a protein, mouse
• Cyclin-Dependent Kinase Inhibitor p16
• beta Catenin

Topics

• Adenomatous Polyposis Coli (genetics, metabolism)
• Adenomatous Polyposis Coli Protein (genetics, metabolism)
• Animals
• Cells, Cultured
• Cyclin-Dependent Kinase Inhibitor p16 (genetics, metabolism)
• Epigenesis, Genetic
• Gene Expression Regulation, Neoplastic
• Humans
• Liver (metabolism, pathology)
• Liver Neoplasms (genetics, metabolism, pathology)
• Mice
• Mice, Transgenic
• Signal Transduction
• beta Catenin (metabolism)