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

Feng, Gui Jie, Cotta, Welwyn, Wei, Xiao-Qing, Poetz, Oliver, Evans, Rebecca Jane, Jardé, Thierry, Reed, Karen Ruth, Meniel, Valerie, Williams, Geraint Trefor, Clarke, Alan Richard and Dale, Trevor Clive 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: 10 Oct 2019 03:01
URI: http://orca.cf.ac.uk/id/eprint/37853

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