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
|
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: | Schools > Biosciences Schools > Dentistry Research Institutes & Centres > European Cancer Stem Cell Research Institute (ECSCRI) Schools > 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: | 04 Apr 2025 21:19 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/37853 |
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