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

Gui Jie Feng, Welwyn Cotta, Xiao-Qing Wei, Oliver Poetz, Rebecca Evans, Thierry Jarde, Karen Reed, Valerie S Meniel, Geraint T Williams, Alan R Clarke, Trevor Dale

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25 Citations (Scopus)

Abstract

BACKGROUND AIMS: Mutations in components of the Wnt signaling pathway, including beta-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 beta-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 G(2)/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 beta-catenin or cause changes in liver zonation that have been associated with loss of the adenomatous polyposis coli (APC) or constitutive activation of beta-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 beta-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.
Original languageEnglish
Pages (from-to)1650 - 1659
Number of pages10
JournalGastroenterology
Volume143
Issue number6
DOIs
Publication statusPublished - 2012
Externally publishedYes

Cite this

Feng, G. J., Cotta, W., Wei, X-Q., Poetz, O., Evans, R., Jarde, T., Reed, K., Meniel, V. S., Williams, G. T., Clarke, A. R., & Dale, T. (2012). Conditional disruption of Axin1 leads to development of liver tumors in mice. Gastroenterology, 143(6), 1650 - 1659. https://doi.org/10.1053/j.gastro.2012.08.047