Loss of Single Immunoglobulin Interlukin-1 Receptor-Related Molecule Leads to Enhanced Colonic Polyposis in Apcmin Mice

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 nonquanritative or quantitative polymerase chain reaction. RESULTS: Apc(min/+/)Sigirr(-/-) mice had increased loss of heterozygosity of Apc and microadenoma formation, resulting in spontaneous colonic polyposis, compared with Apc(min/+/)Sigirr(-/-) mice. The increased colonic tumorigenesis that occurred in the Apc(min/+/)Sigirr(-/-) depended on the presence of commensal bacteria in the gastrointestinal tract. Cell proliferation and chromosomal instability increased in colon crypt cells of the Apc(min/+/)Sigirr(-/-) mice. Akt, mTOR, and their substrates were hyperactivated in colon epithelium of Apc(min/+/)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 Apc(min/+/)Sigirr(-/-) mice. CONCLUSIONS: SIGIRR acts as a tumor suppressor in the colon by inhibiting TLR-induced, mTOR-mediated cell-cycle progression and genetic instability.