ArticleGastroenterology2015
Human Colon Tumors Express a Dominant-Negative Form of SIGIRR That Promotes Inflammation and Colitis-Associated Colon Cancer in Mice.
Article in Gastroenterology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 63 citations in OpenAlex.
- IL-37/IL-1R8 axis: a novel major mechanism of control at the interface between tumor and immune cells.Oncoimmunology · 2026Review
- Interplay between pathogen-mediated immune evasion and innate immune negative regulation in gastrointestinal tumors.Frontiers in immunology · 2026Review
- Interpretable Multimodal Fusion Model for Bridged Histology and Genomics Survival Prediction in Pan-Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- The nuclear cytokine IL-37a controls lethal cytokine storms primarily via IL-1R8-independent transcriptional upregulation of PPARγ.Cellular & molecular immunology · 2023Article
- Naphthaleneoxypropargyl-Containing Piperazine as a Regulator of Effector Immune Cell Populations upon an Aseptic Inflammation.Molecules (Basel, Switzerland) · 2023Article
- Short-chain fatty acids ameliorate necrotizing enterocolitis-like intestinal injury through enhancing Notch1-mediated single immunoglobulin interleukin-1-related receptor, toll-interacting protein, and A20 induction.American journal of physiology. Gastrointestinal and liver physiology · 2023Article
- SIGIRR deficiency contributes to CD4 T cell abnormalities by facilitating the IL1/C/EBPβ/TNF-α signaling axis in rheumatoid arthritis.Molecular medicine (Cambridge, Mass.) · 2022Article
- Dominant-Negative Form of SIGIRR: SIGIRRJournal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research · 2022Article
- A Splice Switch in SIGIRR Causes a Defect of IL-37-Dependent Anti-Inflammatory Activity in Cystic Fibrosis Airway Epithelial Cells.International journal of molecular sciences · 2022Article
- Negative Regulation of the IL-1 System by IL-1R2 and IL-1R8: Relevance in Pathophysiology and Disease.Frontiers in immunology · 2022Review
- The Prognostic Value and Mechanisms of TMEM16A in Human Cancer.Frontiers in molecular biosciences · 2021Review
- Functional genomics analysis of human colon organoids identifies key transcription factors.Physiological genomics · 2020Article
- Inflammation mobilizes copper metabolism to promote colon tumorigenesis via an IL-17-STEAP4-XIAP axis.Nature communications · 2020Article
- The Role of Interleukins in Colorectal Cancer.International journal of biological sciences · 2020Review
- IL1R8 Deficiency Drives Autoimmunity-Associated Lymphoma Development.Cancer immunology research · 2019Article
- Review
- IL-37: An anti-inflammatory cytokine with antitumor functions.Cancer reports (Hoboken, N.J.) · 2019Review
- Tuning inflammation and immunity by the negative regulators IL-1R2 and IL-1R8.Immunological reviews · 2018Review
- High IL-1R8 expression in breast tumors promotes tumor growth and contributes to impaired antitumor immunity.Oncotarget · 2017Article
- Glioblastoma Cancer Stem Cells Evade Innate Immune Suppression of Self-Renewal through Reduced TLR4 Expression.Cell stem cell · 2017Article
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Authors and funding
14 authors at 3 institutions in 1 country.
Funding
Abstract
BACKGROUND &
aimsSingle immunoglobulin and toll-interleukin 1 receptor (SIGIRR), a negative regulator of the Toll-like and interleukin-1 receptor (IL-1R) signaling pathways, controls intestinal inflammation and suppresses colon tumorigenesis in mice. However, the importance of SIGIRR in human colorectal cancer development has not been determined. We investigated the role of SIGIRR in development of human colorectal cancer.
methodsWe performed RNA sequence analyses of pairs of colon tumor and nontumor tissues, each collected from 68 patients. Immunoblot and immunofluorescence analyses were used to determine levels of SIGIRR protein in primary human colonic epithelial cells, tumor tissues, and colon cancer cell lines. We expressed SIGIRR and mutant forms of the protein in Vaco cell lines. We created and analyzed mice that expressed full-length (control) or a mutant form of Sigirr (encoding SIGIRR(N86/102S), which is not glycosylated) specifically in the intestinal epithelium. Some mice were given azoxymethane (AOM) and dextran sulfate sodium to induce colitis-associated cancer. Intestinal tissues were collected and analyzed by immunohistochemical and gene expression profile analyses.
resultsRNA sequence analyses revealed increased expression of a SIGIRR mRNA isoform, SIGIRR(ΔE8), in colorectal cancer tissues compared to paired nontumor tissues. SIGIRR(ΔE8) is not modified by complex glycans and is therefore retained in the cytoplasm-it cannot localize to the cell membrane or reduce IL1R signaling. SIGIRR(ΔE8) interacts with and has a dominant-negative effect on SIGIRR, reducing its glycosylation, localization to the cell surface, and function. Most SIGIRR detected in human colon cancer tissues was cytoplasmic, whereas in nontumor tissues it was found at the cell membrane. Mice that expressed SIGIRR(N86/102S) developed more inflammation and formed larger tumors after administration of azoxymethane and dextran sulfate sodium than control mice; colon tissues from these mutant mice expressed higher levels of the inflammatory cytokines IL-17A and IL-6 had activation of the transcription factors STAT3 and NFκB. SIGIRR(N86/102S) expressed in colons of mice did not localize to the epithelial cell surface.
conclusionLevels of SIGIRR are lower in human colorectal tumors, compared with nontumor tissues; tumors contain the dominant-negative isoform SIGIRR(ΔE8). This mutant protein blocks localization of full-length SIGIRR to the surface of colon epithelial cells and its ability to downregulate IL1R signaling. Expression of SIGIRR(N86/102S) in the colonic epithelium of mice increases expression of inflammatory cytokines and formation and size of colitis-associated tumors.
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