Loss of interleukin-17 receptor D promotes chronic inflammation-associated tumorigenesis
- 11 November 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 40 (2), 452-464
- https://doi.org/10.1038/s41388-020-01540-4
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.Funding Information
- Cancer Research Society (19469)
This publication has 43 references indexed in Scilit:
- Interleukin-17 receptor D constitutes an alternative receptor for interleukin-17A important in psoriasis-like skin inflammationScience Immunology, 2019
- IL-17 and colorectal cancer: From carcinogenesis to treatmentCytokine, 2019
- Roles for Interleukin 17 and Adaptive Immunity in Pathogenesis of Colorectal CancerGastroenterology, 2018
- Interleukin 17 Family Cytokines: Signaling Mechanisms, Biological Activities, and Therapeutic ImplicationsCold Spring Harbor Perspectives in Biology, 2017
- IL-17 in Chronic Inflammation: From Discovery to TargetingTrends in Molecular Medicine, 2016
- Interleukin-17 Receptor A Signaling in Transformed Enterocytes Promotes Early Colorectal TumorigenesisImmunity, 2014
- Innate IL-17-producing cells: the sentinels of the immune systemNature Reviews Immunology, 2010
- A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responsesNature Medicine, 2009
- Structure and signalling in the IL-17 receptor familyNature Reviews Immunology, 2009
- Identification of Sef, a novel modulator of FGF signallingNature, 2002