The 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).
The 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.
We 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-36γ, 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.
Collectively, 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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The datasets analysed during the current study are available publically, as outlined in Table 1. The data underlying this article will be shared on a reasonable request to the corresponding author.
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This work was funded by a grant from the Government of Ireland Postgraduate Scholarship Scheme GOIPG/2018/2974.
The authors declare no competing interests.
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The study was approved by the University College Cork Clinical Research Ethics Committee of the Cork Teaching Hospitals (ECM (3) P 3 September 2013). All samples were obtained during surgery at the Mercy University Hospital Cork following informed consent.
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Baker, K.J., Brint, E. & Houston, A. Transcriptomic and functional analyses reveal a tumour-promoting role for the IL-36 receptor in colon cancer and crosstalk between IL-36 signalling and the IL-17/ IL-23 axis. Br J Cancer 128, 735–747 (2023). https://doi.org/10.1038/s41416-022-02083-z
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