title: Loss of single immunoglobulin interlukin-1 receptor-related molecule leads to enhanced colonic polyposis in Apc(min) mice.
abstract: OBJECTIVE
  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.affiliation: Department of Immunology, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Xiao
authors.forename: Weiguo
authors.initials: W
authors.lastname: Yin
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Khan
authors.forename: Muhammet F
authors.initials: MF
authors.lastname: Gulen
authors.forename: Hang
authors.initials: H
authors.lastname: Zhou
authors.forename: Ho Pan
authors.initials: HP
authors.lastname: Sham
authors.forename: Kevan
authors.initials: K
authors.lastname: Jacobson
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Vallance
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D043171:Chromosomal Instability; D003106:Colon / Q000187:drug effects / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D017491:Genes, APC; D016147:Genes, Tumor Suppressor; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D019656:Loss of Heterozygosity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000172:deficiency* / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D051193:Toll-Like Receptors / Q000378:metabolism; D047368:Tumor Burden; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495267:CTNNB1 protein, mouse; D016207:Cytokines; D018836:Inflammation Mediators; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D017472:Receptors, Interleukin-1; C484529:SIGIRR protein, mouse; D051193:Toll-Like Receptors; D051176:beta Catenin; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus