High Frequency of β-Catenin Mutations in Mouse Hepatocellular Carcinomas Induced by a Nongenotoxic Constitutive Androstane Receptor Agonist.

Abstract

Activation of Wnt/β-catenin signaling is frequent in human and rodent hepatocarcinogenesis. Although in mice the tumor-promoting activity of agonists of constitutive androstane receptor (CAR) occurs by selection of carcinogen-initiated cells harboring β-catenin mutations, the molecular alterations leading to hepatocellular carcinoma (HCC) development by the CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCP) in the absence of genotoxic injury are unknown. Here, we show that CAR activation per se induced HCC in mice and that 91% of them carried β-catenin point mutations or large in-frame deletions/exon skipping targeting Ctnnb1 exon 3. Point mutations in HCCs induced by TCP alone displayed different nucleotide substitutions compared with those found in HCCs from mice pretreated with diethylnitrosamine. Moreover, unlike those occurring in HCCs from diethylnitrosamine + TCP mice, they did not result in increased expression of β-catenin target genes, such as Glul, Lgr5, Rgn, Lect2, Tbx3, Axin2, and Ccnd1, or nuclear translocation of β-catenin compared with the control liver. Remarkably, in the nontumoral liver tissue, chronic CAR activation led to down-regulation of these genes and to a partial loss of glutamine synthetase-positive hepatocytes. These results show that, although chronic CAR activation per se induces HCCs carrying β-catenin mutations, it concurrently down-regulates the Wnt/β-catenin pathway in nontumoral liver. They also indicate that the relationship between CAR and β-catenin may be profoundly different between normal and neoplastic hepatocytes.

• Authors: Sandra Mattu, Christian Saliba, Pia Sulas, Patrizia Zavattari, Andrea Perra, Marta A Kowalik, Satdarshan P Monga, Amedeo Columbano
• Journal: The American journal of pathology (Am J Pathol) Vol. 188 Issue 11 Pg. 2497-2507 (11 2018) ISSN: 1525-2191 [Electronic] United States
• PMID: 30201494 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• CTNNB1 protein, mouse
• Constitutive Androstane Receptor
• Pyridines
• Receptors, Cytoplasmic and Nuclear
• beta Catenin
• 1,4-bis(2-(3,5-dichloropyridyloxy))benzene

Topics

• Animals
• Carcinoma, Hepatocellular (chemically induced, genetics, pathology)
• Constitutive Androstane Receptor
• Female
• Liver Neoplasms, Experimental (chemically induced, genetics, pathology)
• Mice
• Mice, Inbred C3H
• Mutation
• Pyridines (toxicity)
• Receptors, Cytoplasmic and Nuclear (agonists)
• beta Catenin (genetics)