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Cellular and Molecular

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

British Journal of Cancer volume 128, pages 735–747 (2023)Cite this article

Subjects

Abstract

Background

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).

Methods

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.

Results

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.

Conclusions

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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Fig. 1: Expression of IL-36R is increased in multiple malignant tissues relative to normal adjacent tissue.
Fig. 2: IL-36 family member expression is altered in CRC disease development with expression of the IL-36R increased in neoplastic tissue relative to normal tissue in multiple anatomical sites across the intestine.
Fig. 3: High expression of IL-36R is associated with a poorer patient 5-year survival rate in CRC.
Fig. 4: High expression of IL-36R in CRC is associated with IL-17 signalling pathway genes.
Fig. 5: IL-36 and IL-17 signalling genes are associated in vitro and ex vivo.
Fig. 6: IL-36 cytokines, in combination with IL-17 or IL-22, can synergistically induce chemokine expression in CRC cells.

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Data availability

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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Funding

This work was funded by a grant from the Government of Ireland Postgraduate Scholarship Scheme GOIPG/2018/2974.

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Author notes

  1. These authors contributed equally: Elizabeth Brint, Aileen Houston.

Authors and Affiliations

  1. Department of Pathology, University College Cork, Cork, Ireland

    Kevin James Baker & Elizabeth Brint

  2. Department of Medicine, University College Cork, Cork, Ireland

    Kevin James Baker & Aileen Houston

  3. APC Microbiome Ireland, University College Cork, Cork, Ireland

    Kevin James Baker, Elizabeth Brint & Aileen Houston

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  1. Kevin James Baker
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Contributions

KJB conceived and designed work, performed both transcriptomic analysis and experimental work and was involved in the writing of the manuscript. EB and AH conceived and designed work, undertook the data analysis and writing of the manuscript.

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Correspondence to Elizabeth Brint.

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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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