IL-36 signalling enhances a pro-tumorigenic phenotype in colon cancer cells with cancer cell growth restricted by administration of the IL-36R antagonist.

Baker, Kevin; O'Donnell, Charlotte; Bendix, Maura; Keogh, Samuel; Byrne, James; O'Riordain, Michael; Neary, Peter; Houston, Aileen M.; Brint, Elizabeth

IL-36 signalling enhances a pro-tumorigenic phenotype in colon cancer cells with cancer cell growth restricted by administration of the IL-36R antagonist.

dc.contributor.author	Baker, Kevin
dc.contributor.author	O'Donnell, Charlotte
dc.contributor.author	Bendix, Maura
dc.contributor.author	Keogh, Samuel
dc.contributor.author	Byrne, James
dc.contributor.author	O'Riordain, Michael
dc.contributor.author	Neary, Peter
dc.contributor.author	Houston, Aileen M.
dc.contributor.author	Brint, Elizabeth
dc.contributor.funder	Science Foundation Ireland	en
dc.contributor.funder	Government of Ireland	en
dc.contributor.funder	Irish Research eLibrary	en
dc.date.accessioned	2022-12-06T14:42:25Z
dc.date.available	2022-12-06T14:42:25Z
dc.date.issued	2022-04-22
dc.date.updated	2022-11-25T12:36:45Z
dc.description.abstract	The IL-36 cytokines are a recently described subset of the IL-1 family of cytokines, shown to play a role in the pathogenesis of intestinal diseases such as Inflammatory Bowel Disease (IBD). Given the link between IBD and colitis -associated cancer, as well as the involvement of other IL-1 family members in intestinal tumorigenesis, the aim of this work was to investigate whether IL-36 cytokines play a role in the pathogenesis of colon cancer. Whilst research to date has focused on the role of IL-36 family members in augmenting the immune response to induce tumour rejection, very little remains known about IL-36R signalling in tumour cells in this context. In this study we demonstrate that expression of IL-36 family member mRNA and protein are significantly increased in colorectal cancer tissue compared to adjacent non-tumour. In vitro assays showed stimulation of colon cancer cell lines with IL-36R agonists resulted in the activation of the pro-tumorigenic phenotypes of increased cellular migration, invasion and proliferation in both 2D and 3D models. In addition, the IL-36 cytokines induced strong expression of pro-inflammatory chemokines in both human and murine cell lines. Intraperitoneal injection of IL-36Ra significantly reduced tumour burden using the subcutaneous CT26 tumour model in syngeneic Balb/mice, and this was associated with a decrease in Ki-67 expression by tumour cells in the IL-36Ra- treated group relative to untreated, suggesting the inhibition of the pro-proliferative signalling of IL-36 agonists resulted in the decreased tumour size. Moreover, colon cancer cells lacking the IL-36R also showed reduced tumour growth and reduced Ki-67 expression in vivo. Taken together, this data suggests that targeting IL-36R signalling may be a useful targeted therapy for colorectal cancer patients with IL-36R+ tumour cells.	en
dc.description.sponsorship	Government of Ireland (postgraduate scholarship scheme GOIPG/2018/2974); Irish Research eLibrary (Open Access funding provided by the IReL Consortium)	en
dc.description.status	Peer reviewed	en
dc.description.version	Published Version	en
dc.format.mimetype	application/pdf	en
dc.identifier.citation	Baker, K., O’Donnell, C., Bendix, M., Keogh, S., Byrne, J., O’Riordain, M., Neary, P., Houston, A., and Brint, E. (2022) ‘IL-36 signalling enhances a pro-tumorigenic phenotype in colon cancer cells with cancer cell growth restricted by administration of the IL-36R antagonist’, Oncogene, 41(19), pp. 2672–2684. https://doi.org/10.1038/s41388-022-02281-2	en
dc.identifier.doi	10.1038/s41388-022-02281-2	en
dc.identifier.endpage	2684	en
dc.identifier.issn	1476-5594
dc.identifier.issued	19	en
dc.identifier.journaltitle	Oncogene	en
dc.identifier.startpage	2672	en
dc.identifier.uri	https://hdl.handle.net/10468/13900
dc.identifier.volume	41	en
dc.language.iso	en	en
dc.publisher	Springer Nature	en
dc.relation.uri	https://doi.org/10.1038/s41388-022-02281-2
dc.rights	© The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made…	en
dc.rights.uri	http://creativecommons.org/licenses/by/4.0/	en
dc.subject	Inflammatory Bowel Disease (IBD)	en
dc.subject	Colitis	en
dc.subject	Colorectal cancer (CRC)	en
dc.subject	IL-36 cytokines	en
dc.title	IL-36 signalling enhances a pro-tumorigenic phenotype in colon cancer cells with cancer cell growth restricted by administration of the IL-36R antagonist.	en
dc.type	Article (peer-reviewed)	en