Conditional disruption of Axin1 leads to development of liver tumors in mice

Feng, Gui Jie, Cotta, Welwyn, Wei, Xiao-Qing ORCID: https://orcid.org/0000-0002-6274-8503, Poetz, Oliver, Evans, Rebecca Jane, Jardé, Thierry, Reed, Karen Ruth ORCID: https://orcid.org/0000-0002-7467-1718, Meniel, Valerie, Williams, Geraint Trefor ORCID: https://orcid.org/0000-0003-3768-9940, Clarke, Alan Richard ORCID: https://orcid.org/0000-0002-4281-426X and Dale, Trevor Clive ORCID: https://orcid.org/0000-0002-4880-9963 2012. Conditional disruption of Axin1 leads to development of liver tumors in mice. Gastroenterology 143 (6) , pp. 1650-1659. 10.1053/j.gastro.2012.08.047

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Abstract

Background & Aims: Mutations in components of the Wnt signaling pathway, including β-catenin and AXIN1, are found in more than 50% of human hepatocellular carcinomas (HCCs). Disruption of Axin1 causes embryonic lethality in mice. We generated mice with conditional disruption of Axin1 to study its function specifically in adult liver. Methods: Mice with a LoxP-flanked allele of Axin1 were generated by homologous recombination. Mice homozygous for the Axin1fl/fl allele were crossed with AhCre mice; in offspring, Axin1 was disrupted in liver following injection of β-naphthoflavone (Axin1fl/fl/Cre mice). Liver tissues were collected and analyzed by quantitative real-time polymerase chain reaction and immunoprecipitation, histology, and immunoblot assays. Results: Deletion of Axin1 from livers of adult mice resulted in an acute and persistent increase in hepatocyte cell volume, proliferation, and transcription of genes that induce the G2/M transition in the cell cycle and cytokinesis. A subset of Wnt target genes was activated, including Axin2, c-Myc, and cyclin D1. However, loss of Axin1 did not increase nuclear levels of β-catenin or cause changes in liver zonation that have been associated with loss of the adenomatous polyposis coli (APC) or constitutive activation of β-catenin. After 1 year, 5 of 9 Axin1fl/fl/Cre mice developed liver tumors with histologic features of HCC. Conclusions: Hepatocytes from adult mice with conditional disruption of Axin1 in liver have a transcriptional profile that differs from that associated with loss of APC or constitutive activation of β-catenin. It might be similar to a proliferation profile observed in a subset of human HCCs with mutations in AXIN1. Axin1fl/fl mice could be a useful model of AXIN1-associated tumorigenesis and HCC.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences Dentistry European Cancer Stem Cell Research Institute (ECSCRI) Medicine
Subjects:	Q Science > QH Natural history > QH426 Genetics R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Uncontrolled Keywords:	Mouse Model; Liver Cancer; Carcinogenesis; BNF
Publisher:	Elsevier
ISSN:	0016-5085
Last Modified:	06 Jan 2023 02:06
URI:	https://orca.cardiff.ac.uk/id/eprint/37853

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