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BRITISH JOURNAL OF CANCER
Volume 128, Issue 5, Pages 735-747Publisher
SPRINGERNATURE
DOI: 10.1038/s41416-022-02083-z
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IL-36 cytokines play a crucial role in the pathogenesis of inflammatory diseases and malignancies. This study demonstrates that IL-36 gene expression increases with the development of colorectal cancer and decreased IL-36 receptor expression is associated with better patient outcome. The IL-36/IL-17/IL-23 axis is found to be influential in IL-36-mediated colon tumorigenesis.
BackgroundThe interleukin (IL)-36 cytokines are a sub-family of the IL-1 family which are becoming increasingly implicated in the pathogenesis of inflammatory diseases and malignancies. Initial studies of IL-36 signalling in tumorigenesis identified an immune-mediated anti-tumorigenic function for these cytokines. However, more recent studies have shown IL-36 cytokines also contribute to the pathogenesis of lung and colorectal cancer (CRC). MethodsThe aim of this study was to investigate IL-36 expression in CRC using transcriptomic datasets and software such as several R packages, Cytoscape, GEO2R and AnalyzeR. Validation of results was completed by qRT-PCR on both cell lines and a patient cohort. Cellular proliferation was assessed by flow cytometry and resazurin reduction. ResultsWe demonstrate that IL-36 gene expression increases with CRC development. Decreased tumoral IL-36 receptor expression was shown to be associated with improved patient outcome. Our differential gene expression analysis revealed a novel role for the IL-36/IL-17/IL-23 axis, with these findings validated using patient-derived samples and cell lines. IL-36 gamma, together with either IL-17a or IL-22, was able to synergistically induce different genes involved in the IL-17/IL-23 axis in CRC cells and additively induce colon cancer cell proliferation. ConclusionsCollectively, this data support a pro-tumorigenic role for IL-36 signalling in colon cancer, with the IL-17/IL-23 axis influential in IL-36-mediated colon tumorigenesis.
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