Loss of interleukin-17 receptor D promotes chronic inflammation-associated tumorigenesis

Abstract

Interleukin-17 receptor D (IL-17RD), also known as similar expression to Fgf genes (SEF), is proposed to act as a signaling hub that negatively regulates mitogenic signaling pathways, like the ERK1/2 MAP kinase pathway, and innate immune signaling. The expression of IL-17RD is downregulated in certain solid tumors, which has led to the hypothesis that it may exert tumor suppressor functions. However, the role of IL-17RD in tumor biology remains to be studied in vivo. Here, we show that genetic disruption of Il17rd leads to the increased formation of spontaneous tumors in multiple tissues of aging mice. Loss of IL-17RD also promotes tumor development in a model of colitis-associated colorectal cancer, associated with an exacerbated inflammatory response. Colon tumors from IL-17RD-deficient mice are characterized by a strong enrichment in inflammation-related gene signatures, elevated expression of pro-inflammatory tumorigenic cytokines, such as IL-17A and IL-6, and increased STAT3 tyrosine phosphorylation. We further show that RNAi depletion of IL-17RD enhances Toll-like receptor and IL-17A signaling in colon adenocarcinoma cells. No change in the proliferation of normal or tumor intestinal epithelial cells was observed upon genetic inactivation of IL-17RD. Our findings establish IL-17RD as a tumor suppressor in mice and suggest that the protein exerts its function mainly by limiting the extent and duration of inflammation.

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Fig. 1: IL-17RD suppresses spontaneous tumor formation in aging mice.
Fig. 2: Loss of IL-17RD promotes colitis-associated colorectal tumorigenesis.
Fig. 3: IL-17RD has no cell-autonomous effect on intestinal cell proliferation.
Fig. 4: Loss of IL-17RD exacerbates the inflammatory reaction in colitis-associated colorectal cancer.
Fig. 5: IL-17RD expression restricts DSS-induced intestinal inflammation.
Fig. 6: Downregulation of IL-17RD increases TLR and IL-17 signaling in colorectal cancer cells.
Fig. 7: IL17RD gene expression is downregulated in human colorectal cancer.

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Acknowledgements

We thank C. Kuo and G.R. van den Brink for reagents, J. Hinsinger for histology, L. Gaboury for pathology assistance, P. Melançon for qPCR analysis, J. Huber for RNA-seq, and P. Gendron for help with bioinformatic analyses. CG is recipient of a studentship from the Fonds de recherche Santé Québec. SM held the Canada Research Chair in Cellular Signaling. Work in the Meloche laboratory was supported by a grant from the Cancer Research Society.

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Correspondence to Sylvain Meloche.

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Girondel, C., Lévesque, K., Langlois, MJ. et al. Loss of interleukin-17 receptor D promotes chronic inflammation-associated tumorigenesis. Oncogene (2020). https://doi.org/10.1038/s41388-020-01540-4

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