Loss of single immunoglobulin interlukin-1 receptor-related molecule leads to enhanced colonic polyposis in Apc(min) mice.

Abstract

BACKGROUND & AIMS:

Commensal bacteria can activate signaling by the Toll-like and interleukin-1 receptors (TLR and IL-1R) to mediate pathogenesis of inflammatory bowel diseases and colitis-associated cancer. We investigated the role of the single immunoglobulin IL-1 receptor-related (SIGIRR) molecule, a negative regulator of TLR and IL-1R signaling, as a tumor suppressor to determine whether SIGIRR controls cell-cycle progression, genetic instability, and colon tumor initiation by modulating commensal TLR signaling in the gastrointestinal tract.

METHODS:

We analyzed adenomatous polyposis coli (Apc)min/+/Sigirr-/- mice for polyps, microadenomas, and anaphase bridge index. Commensal bacteria were depleted from mice with antibiotics. Akt, mammalian target of rapamycin (mTOR), and beta-catenin pathways were examined by immunoblotting and immunohistochemistry. Loss of heterozygosity of Apc and expression of cytokines and proinflammatory mediators were measured by nonquantitative or quantitative polymerase chain reaction.

RESULTS:

Apcmin/+/Sigirr-/- mice had increased loss of heterozygosity of Apc and microadenoma formation, resulting in spontaneous colonic polyposis, compared with Apcmin/+/Sigirr+/+ mice. The increased colonic tumorigenesis that occurred in the Apcmin/+/Sigirr-/- mice depended on the presence of commensal bacteria in the gastrointestinal tract. Cell proliferation and chromosomal instability increased in colon crypt cells of the Apcmin/+/Sigirr-/- mice. Akt, mTOR, and their substrates were hyperactivated in colon epithelium of Apcmin/+/Sigirr-/- mice in response to TLR or IL-1R ligands. Inhibition of the mTOR pathway by rapamycin reduced formation of microadenomas and polyps in the Apcmin/+/Sigirr-/- mice.

CONCLUSIONS:

SIGIRR acts as a tumor suppressor in the colon by inhibiting TLR-induced, mTOR-mediated cell-cycle progression and genetic instability.

• Authors: Hui Xiao, Weiguo Yin, Mohammed A Khan, Muhammet F Gulen, Hang Zhou, Ho Pan Sham, Kevan Jacobson, Bruce A Vallance, Xiaoxia Li
• Journal: Gastroenterology (Gastroenterology) Vol. 139 Issue 2 Pg. 574-85 (Aug 2010) ISSN: 1528-0012 [Electronic] United States
• PMID: 20416302 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright (c) 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• CTNNB1 protein, mouse
• Cytokines
• Inflammation Mediators
• Intracellular Signaling Peptides and Proteins
• Protein Kinase Inhibitors
• Receptors, Interleukin-1
• SIGIRR protein, mouse
• Toll-Like Receptors
• beta Catenin
• mTOR protein, mouse
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Sirolimus

Topics

• Adenomatous Polyposis Coli (genetics, metabolism, microbiology, pathology, prevention & control)
• Animals
• Blotting, Western
• Cell Proliferation
• Chromosomal Instability
• Colon (drug effects, metabolism, microbiology, pathology)
• Cytokines (metabolism)
• Genes, APC
• Genes, Tumor Suppressor
• Immunohistochemistry
• Inflammation Mediators (metabolism)
• Intestinal Mucosa (metabolism)
• Intracellular Signaling Peptides and Proteins (antagonists & inhibitors, metabolism)
• Loss of Heterozygosity
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Mutant Strains
• Protein Kinase Inhibitors (pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptors, Interleukin-1 (deficiency, genetics)
• Sirolimus (pharmacology)
• TOR Serine-Threonine Kinases
• Toll-Like Receptors (metabolism)
• Tumor Burden
• beta Catenin (metabolism)