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

• Published in: British journal of cancer Vol. 128; no. 5; pp. 735 - 747
• Main Authors: Baker, Kevin James, Brint, Elizabeth, Houston, Aileen
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.03.2023; Nature Publishing Group
• Subjects: 631/67/580; 692/4028; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinogenesis; Cell proliferation; Colon cancer; Colonic Neoplasms; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - pathology; Cytokines; Cytokines - metabolism; Drug Resistance; Epidemiology; Flow cytometry; Gene expression; Gene Expression Profiling; Humans; Inflammatory diseases; Interleukin 1; Interleukin 17; Interleukin 22; Interleukin 23; Interleukin-23 - genetics; Lung cancer; Malignancy; Molecular Medicine; Oncology; Pathogenesis; Transcriptome; Transcriptomics; Tumorigenesis; Tumors
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-022-02083-z

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.