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

Ueberham, E. et al. (2015) Global increase of p16INK4a in APC-deficient mouse liver drives clonal growth of p16INK4a-negative tumors. Molecular Cancer Research, 13(2), pp. 239-249. (doi:10.1158/1541-7786.MCR-14-0278-T) (PMID:25270420)

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Abstract

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 p16INK4a 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 p16INK4a, by epigenetic silencing, drives the development of liver tumors in mice with reduced APC expression (Apc580S mice). The lack of p16INK4a was also detected in liver tumors of mice with triggers other than APC reduction.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Sansom, Professor Owen
Authors: Ueberham, E., Glockner, P., Gohler, C., Straub, B.K., Teupser, D., Schonig, K., Braeuning, A., Hohn, A.K., Jerchow, B., Birchmeier, W., Gaunitz, F., Arendt, T., Sansom, O., Gebhardt, R., and Ueberham, U.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Molecular Cancer Research
Publisher:American Association for Cancer Research
ISSN:1541-7786
ISSN (Online):1557-3125

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