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Loss of Adenomatous polyposis coli function renders intestinal epithelial cells resistant to the cytokine IL-22

View ORCID ProfileYu Chen, View ORCID ProfileIan P. Newton, View ORCID ProfileMaud Vandereyken, View ORCID ProfileIgnacio Moraga, View ORCID ProfileInke Näthke, View ORCID ProfileMahima Swamy
doi: https://doi.org/10.1101/479972
Yu Chen
1Cell and Developmental Biology, University of Dundee, Dundee, DD1 5EH, UK
2MRC Protein Phosphorylation and Ubiquitylation Unit (PPU), University of Dundee, Dundee, DD1 5EH, UK
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Ian P. Newton
1Cell and Developmental Biology, University of Dundee, Dundee, DD1 5EH, UK
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Maud Vandereyken
2MRC Protein Phosphorylation and Ubiquitylation Unit (PPU), University of Dundee, Dundee, DD1 5EH, UK
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Ignacio Moraga
3Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK
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Inke Näthke
1Cell and Developmental Biology, University of Dundee, Dundee, DD1 5EH, UK
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  • For correspondence: m.swamy@dundee.ac.uk i.s.nathke@dundee.ac.uk
Mahima Swamy
2MRC Protein Phosphorylation and Ubiquitylation Unit (PPU), University of Dundee, Dundee, DD1 5EH, UK
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  • For correspondence: m.swamy@dundee.ac.uk i.s.nathke@dundee.ac.uk
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Abstract

Interleukin-22 (IL-22) is critical in maintaining homeostasis in the intestine by regulating the balance between pathogenic and commensal bacteria. IL-22 also promotes wound healing and tissue regeneration, which can support the growth of colorectal tumours. Mutations in the tumour suppressor Adenomatous Polyposis Coli gene (Apc) cause intestinal tumorigenesis and are a major driver of familial colorectal cancers. To understand the role of IL-22 in APC-mediated tumorigenesis, we analysed IL-22 signalling in wild-type (WT) and APC-mutant cells in murine small intestinal epithelial organoids and in mice. In WT epithelia, antimicrobial defence, mucus production, and cellular stress response pathways were most strongly upregulated by IL-22. Surprisingly, we found that although IL-22 activated STAT3 in APC-mutant cells, STAT3 target genes were not effectively induced. Our analyses revealed that ApcMin/Min cells were resistant to IL-22 due to reduced expression of the IL-22 receptor, and increased expression of inhibitors of STAT3, including histone deacetylases. We further show that IL-22 induced expression of nitric oxide synthase in WT epithelial cells and corresponding DNA damage. These findings suggest that IL-22 does not promotes tumour formation by driving the proliferation of transformed intestinal epithelial cells. Rather, IL-22 increases genetic instability thereby accelerating transition from heterozygosity (ApcMin/+) to homozygosity (ApcMin/Min) to drive tumour progression.

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Posted December 01, 2018.
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Loss of Adenomatous polyposis coli function renders intestinal epithelial cells resistant to the cytokine IL-22
Yu Chen, Ian P. Newton, Maud Vandereyken, Ignacio Moraga, Inke Näthke, Mahima Swamy
bioRxiv 479972; doi: https://doi.org/10.1101/479972
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Loss of Adenomatous polyposis coli function renders intestinal epithelial cells resistant to the cytokine IL-22
Yu Chen, Ian P. Newton, Maud Vandereyken, Ignacio Moraga, Inke Näthke, Mahima Swamy
bioRxiv 479972; doi: https://doi.org/10.1101/479972

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