Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Oncogene volume 40, pages 452–464 (2021)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Monin L, Gaffen SL. Interleukin 17 family cytokines: signaling mechanisms, biological activities, and therapeutic implications. Cold Spring Harb Perspect Biol. 2018;10:a028522.

    PubMed  PubMed Central  Google Scholar 

  2. Cua DJ, Tato CM. Innate IL-17-producing cells: the sentinels of the immune system. Nat Rev Immunol. 2010;10:479–89.

    CAS  PubMed  Google Scholar 

  3. Beringer A, Noack M, Miossec P. IL-17 in chronic inflammation: from discovery to targeting. Trends Mol Med. 2016;22:230–41.

    CAS  PubMed  Google Scholar 

  4. Wang K, Kim MK, Di Caro G, Wong J, Shalapour S, Wan J, et al. Interleukin-17 receptor a signaling in transformed enterocytes promotes early colorectal tumorigenesis. Immunity. 2014;41:1052–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Hurtado CG, Wan F, Housseau F, Sears CL. Roles for interleukin 17 and adaptive immunity in pathogenesis of colorectal cancer. Gastroenterology. 2018;155:1706–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Razi S, Baradaran Noveiry B, Keshavarz-Fathi M, Rezaei N. IL-17 and colorectal cancer: from carcinogenesis to treatment. Cytokine. 2019;116:7–12.

    CAS  PubMed  Google Scholar 

  7. Wu S, Rhee KJ, Albesiano E, Rabizadeh S, Wu X, Yen HR, et al. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat Med. 2009;15:1016–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Gaffen SL. Structure and signalling in the IL-17 receptor family. Nat Rev Immunol. 2009;9:556–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Su Y, Huang J, Zhao X, Lu H, Wang W, Yang XO, et al. Interleukin-17 receptor D constitutes an alternative receptor for interleukin-17A important in psoriasis-like skin inflammation. Sci Immunol. 2019;4:eaau9657.

    CAS  PubMed  Google Scholar 

  10. Tsang M, Friesel R, Kudoh T, Dawid IB. Identification of Sef, a novel modulator of FGF signalling. Nat Cell Biol. 2002;4:165–9.

    CAS  PubMed  Google Scholar 

  11. Furthauer M, Lin W, Ang SL, Thisse B, Thisse C. Sef is a feedback-induced antagonist of Ras/MAPK-mediated FGF signalling. Nat Cell Biol. 2002;4:170–4.

    CAS  PubMed  Google Scholar 

  12. Ron D, Fuchs Y, Chorev DS. Know thy Sef: a novel class of feedback antagonists of receptor tyrosine kinase signaling. Int J Biochem Cell Biol. 2008;40:2040–52.

    CAS  PubMed  Google Scholar 

  13. Kovalenko D, Yang X, Nadeau RJ, Harkins LK, Friesel R. Sef inhibits fibroblast growth factor signaling by inhibiting FGFR1 tyrosine phosphorylation and subsequent ERK activation. J Biol Chem. 2003;278:14087–91.

    CAS  PubMed  Google Scholar 

  14. Ren Y, Cheng L, Rong Z, Li Z, Li Y, Li H, et al. hSef co-localizes and interacts with Ras in the inhibition of Ras/MAPK signaling pathway. Biochem Biophys Res Commun. 2006;347:988–93.

    CAS  PubMed  Google Scholar 

  15. Torii S, Kusakabe M, Yamamoto T, Maekawa M, Nishida E. Sef is a spatial regulator for Ras/MAP kinase signaling. Dev Cell. 2004;7:33–44.

    CAS  PubMed  Google Scholar 

  16. Duhamel S, Hébert J, Gaboury L, Bouchard A, Simon R, Sauter G, et al. Sef downregulation by Ras causes MEK1/2 to become aberrantly nuclear localized leading to polyploidy and neoplastic transformation. Cancer Res. 2012;72:626–35.

    CAS  PubMed  Google Scholar 

  17. Ren Y, Cheng L, Rong Z, Li Z, Li Y, Zhang X, et al. hSef potentiates EGF-mediated MAPK signaling through affecting EGFR trafficking and degradation. Cell Signal. 2008;20:518–33.

    CAS  PubMed  Google Scholar 

  18. Peng DH, Kundu ST, Fradette JJ, Diao L, Tong P, Byers LA, et al. ZEB1 suppression sensitizes KRAS mutant cancers to MEK inhibition by an IL17RD-dependent mechanism. Sci Transl Med. 2019;11:eaaq1238.

  19. Fuchs Y, Brunwasser M, Haif S, Haddad J, Shneyer B, Goldshmidt-Tran O, et al. Sef is an inhibitor of proinflammatory cytokine signaling, acting by cytoplasmic sequestration of NF-kappaB. Dev Cell. 2012;23:611–23.

    CAS  PubMed  Google Scholar 

  20. Mellett M, Atzei P, Bergin R, Horgan A, Floss T, Wurst W, et al. Orphan receptor IL-17RD regulates Toll-like receptor signalling via SEFIR/TIR interactions. Nat Commun. 2015;6:6669.

    CAS  PubMed  Google Scholar 

  21. Rong Z, Wang A, Li Z, Ren Y, Cheng L, Li Y, et al. IL-17RD (Sef or IL-17RLM) interacts with IL-17 receptor and mediates IL-17 signaling. Cell Res. 2008;19:208–15.

    Google Scholar 

  22. Mellett M, Atzei P, Horgan A, Hams E, Floss T, Wurst W, et al. Orphan receptor IL-17RD tunes IL-17A signalling and is required for neutrophilia. Nat Commun. 2012;3:1119.

    PubMed  Google Scholar 

  23. Darby S, Murphy T, Thomas H, Robson CN, Leung HY, Mathers ME, et al. Similar expression to FGF (Sef) inhibits fibroblast growth factor-induced tumourigenic behaviour in prostate cancer cells and is downregulated in aggressive clinical disease. Br J Cancer. 2009;101:1891–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. He Q, Gong Y, Gower L, Yang X, Friesel RE. Sef regulates epithelial-mesenchymal transition in breast cancer cells. J Cell Biochem. 2016;117:2346–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Darby S, Sahadevan K, Khan MM, Robson CN, Leung HY, Gnanapragasam VJ. Loss of Sef (similar expression to FGF) expression is associated with high grade and metastatic prostate cancer. Oncogene. 2006;25:4122–7.

    CAS  PubMed  Google Scholar 

  26. Zisman-Rozen S, Fink D, Ben-Izhak O, Fuchs Y, Brodski A, Kraus MH, et al. Downregulation of Sef, an inhibitor of receptor tyrosine kinase signaling, is common to a variety of human carcinomas. Oncogene. 2007;26:6093–8.

    CAS  PubMed  Google Scholar 

  27. Parang B, Barrett CW, Williams CS. AOM/DSS model of colitis-associated cancer. Methods Mol Biol. 2016;1422:297–307.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Murphy T, Darby S, Mathers ME, Gnanapragasam VJ. Evidence for distinct alterations in the FGF axis in prostate cancer progression to an aggressive clinical phenotype. J Pathol. 2010;220:452–60.

    CAS  PubMed  Google Scholar 

  29. Taniguchi K, Karin M. NF-kappaB, inflammation, immunity and cancer: coming of age. Nat Rev Immunol. 2018;18:309–24.

    CAS  PubMed  Google Scholar 

  30. Furman D, Campisi J, Verdin E, Carrera-Bastos P, Targ S, Franceschi C, et al. Chronic inflammation in the etiology of disease across the life span. Nat Med. 2019;25:1822–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Fichtner-Feigl S, Kesselring R, Strober W. Chronic inflammation and the development of malignancy in the GI tract. Trends Immunol. 2015;36:451–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Stidham RW, Higgins PDR. Colorectal cancer in inflammatory bowel disease. Clin Colon Rectal Surg. 2018;31:168–78.

    PubMed  PubMed Central  Google Scholar 

  33. Neurath MF. Cytokines in inflammatory bowel disease. Nat Rev Immunol. 2014;14:329–342.

    CAS  PubMed  Google Scholar 

  34. West NR, McCuaig S, Franchini F, Powrie F. Emerging cytokine networks in colorectal cancer. Nat Rev Immunol. 2015;15:615–29.

    CAS  PubMed  Google Scholar 

  35. Taniguchi K, Karin M. IL-6 and related cytokines as the critical lynchpins between inflammation and cancer. Semin Immunol. 2014;26:54–74.

    CAS  PubMed  Google Scholar 

  36. Pekow J, Meckel K, Dougherty U, Huang Y, Chen X, Almoghrabi A, et al. miR-193a-3p is a key tumor suppressor in ulcerative colitis-associated colon cancer and promotes carcinogenesis through upregulation of IL17RD. Clin Cancer Res. 2017;23:5281–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. He Q, Yang X, Gong Y, Kovalenko D, Canalis E, Rosen CJ, et al. Deficiency of Sef is associated with increased postnatal cortical bone mass by regulating Runx2 activity. J Bone Min Res. 2014;29:1217–31.

    CAS  Google Scholar 

  38. Gonneaud A, Jones C, Turgeon N, Levesque D, Asselin C, Boudreau F, et al. A SILAC-based method for quantitative proteomic analysis of intestinal organoids. Sci Rep. 2016;6:38195.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature. 2009;459:262–5.

    CAS  PubMed  Google Scholar 

  40. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102:15545–50.

    CAS  PubMed  Google Scholar 

  41. Liberzon A, Subramanian A, Pinchback R, Thorvaldsdottir H, Tamayo P, Mesirov JP. Molecular signatures database (MSigDB) 3.0. Bioinformatics. 2011;27:1739–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, et al. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015;12:453–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Soulez M, Saba-El-Leil MK, Turgeon B, Mathien S, Coulombe P, Klinger S, et al. Reevaluation of the role of extracellular signal-regulated kinase 3 in perinatal survival and postnatal growth using new genetically engineered mouse models. Mol Cell Biol. 2019;39:e00527–18.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Institute for Research in Immunology and Cancer, Montreal, Quebec, Canada

    Charlotte Girondel, Kim Lévesque, Marc K. Saba-El-Leil & Sylvain Meloche

  2. Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada

    Charlotte Girondel, Sarah Pasquin, Jean-François Gauchat & Sylvain Meloche

  3. Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada

    Marie-Josée Langlois & Nathalie Rivard

  4. Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME, USA

    Robert Friesel

  5. Faculty of Pharmacy, Université de Montréal, Montreal, QC, Canada

    Marc J. Servant

  6. Department of Immunology-Oncology, Maisonneuve-Rosemont Hospital, Montreal, QC, Canada

    Sylvie Lesage

  7. Department of Microbiology, Infectiology and Immunology, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada

    Sylvie Lesage

  8. Molecular Biology Program, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada

    Sylvain Meloche

Authors
  1. Charlotte Girondel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kim Lévesque
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marie-Josée Langlois
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sarah Pasquin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marc K. Saba-El-Leil
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nathalie Rivard
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Robert Friesel
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Marc J. Servant
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jean-François Gauchat
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Sylvie Lesage
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Sylvain Meloche
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sylvain Meloche.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Girondel, C., Lévesque, K., Langlois, MJ. et al. Loss of interleukin-17 receptor D promotes chronic inflammation-associated tumorigenesis. Oncogene 40, 452–464 (2021). https://doi.org/10.1038/s41388-020-01540-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-020-01540-4

This article is cited by

Search

Advanced search

Quick links