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- Title
Loss of adenomatous polyposis coli function renders intestinal epithelial cells resistant to the cytokine IL-22.
- Authors
Chen, Yu; Vandereyken, Maud; Newton, Ian P.; Moraga, Ignacio; Näthke, Inke S.; Swamy, Mahima
- Abstract
Interleukin-22 (IL-22) is a critical immune defence cytokine that maintains intestinal homeostasis and promotes wound healing and tissue regeneration, which can support the growth of colorectal tumours. Mutations in adenomatous polyposis coli gene (Apc) are a major driver of familial colorectal cancers (CRCs). How IL-22 contributes to APC-mediated tumorigenesis is poorly understood. To investigate IL-22 signalling in wild-type (WT) and APC-mutant cells, we performed RNA sequencing (RNAseq) of IL-22–treated murine small intestinal epithelial organoids. In WT epithelia, antimicrobial defence and cellular stress response pathways were most strongly induced by IL-22. Surprisingly, although IL-22 activates signal transducer and activator of transcription 3 (STAT3) in APC-mutant cells, STAT3 target genes are not induced. Our analyses revealed that ApcMin/Min cells are resistant to IL-22 due to reduced expression of the IL-22 receptor, and increased expression of inhibitors of STAT3, particularly histone deacetylases (HDACs). We further show that IL-22 increases DNA damage and genomic instability, which can accelerate cellular transition from heterozygosity (ApcMin/+) to homozygosity (ApcMin/Min) to drive tumour formation. Our data reveal an unexpected role for IL-22 in promoting early tumorigenesis while excluding a function for IL-22 in transformed epithelial cells. The adenomatous polyposis coli (APC) gene is mutated in 85% of colorectal cancers. This study shows that when APC is mutated in murine intestinal epithelial cells, they no longer respond to IL-22, a cytokine that is considered important for colorectal cancer progression; this has implications for IL-22 as a therapeutic target for cancer treatment.
- Subjects
ADENOMATOUS polyposis coli; EPITHELIAL cells; INTERLEUKIN-22; COLON cancer; HOMOZYGOSITY; RNA sequencing; DNA damage; TIGHT junctions
- Publication
PLoS Biology, 2019, Vol 17, Issue 11, p1
- ISSN
1544-9173
- Publication type
Article
- DOI
10.1371/journal.pbio.3000540