PMID- 20416302
OWN - NLM
STAT- MEDLINE
DCOM- 20100812
LR  - 20211203
IS  - 1528-0012 (Electronic)
IS  - 0016-5085 (Print)
IS  - 0016-5085 (Linking)
VI  - 139
IP  - 2
DP  - 2010 Aug
TI  - Loss of single immunoglobulin interlukin-1 receptor-related molecule leads to 
      enhanced colonic polyposis in Apc(min) mice.
PG  - 574-85
LID - 10.1053/j.gastro.2010.04.043 [doi]
AB  - 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.
CI  - Copyright (c) 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
FAU - Xiao, Hui
AU  - Xiao H
AD  - Department of Immunology, Cleveland Clinic Foundation, Cleveland, Ohio 44195, 
      USA.
FAU - Yin, Weiguo
AU  - Yin W
FAU - Khan, Mohammed A
AU  - Khan MA
FAU - Gulen, Muhammet F
AU  - Gulen MF
FAU - Zhou, Hang
AU  - Zhou H
FAU - Sham, Ho Pan
AU  - Sham HP
FAU - Jacobson, Kevan
AU  - Jacobson K
FAU - Vallance, Bruce A
AU  - Vallance BA
FAU - Li, Xiaoxia
AU  - Li X
LA  - eng
GR  - R01 AI060632/AI/NIAID NIH HHS/United States
GR  - R01 AI060632-05/AI/NIAID NIH HHS/United States
GR  - CAPMC/CIHR/Canada
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100421
PL  - United States
TA  - Gastroenterology
JT  - Gastroenterology
JID - 0374630
RN  - 0 (CTNNB1 protein, mouse)
RN  - 0 (Cytokines)
RN  - 0 (Inflammation Mediators)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Receptors, Interleukin-1)
RN  - 0 (SIGIRR protein, mouse)
RN  - 0 (Toll-Like Receptors)
RN  - 0 (beta Catenin)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adenomatous Polyposis 
      Coli/genetics/*metabolism/microbiology/pathology/*prevention & control
MH  - Animals
MH  - Blotting, Western
MH  - Cell Proliferation
MH  - Chromosomal Instability
MH  - Colon/drug effects/*metabolism/microbiology/pathology
MH  - Cytokines/metabolism
MH  - *Genes, APC
MH  - *Genes, Tumor Suppressor
MH  - Immunohistochemistry
MH  - Inflammation Mediators/metabolism
MH  - Intestinal Mucosa/metabolism
MH  - Intracellular Signaling Peptides and Proteins/antagonists & inhibitors/metabolism
MH  - Loss of Heterozygosity
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Mice, Mutant Strains
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Protein Serine-Threonine Kinases/antagonists & inhibitors/metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Receptors, Interleukin-1/*deficiency/genetics
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Toll-Like Receptors/metabolism
MH  - Tumor Burden
MH  - beta Catenin/metabolism
PMC - PMC3261756
MID - NIHMS199559
COIS- There is no conflict of interest to disclosure for all the authors.
EDAT- 2010/04/27 06:00
MHDA- 2010/08/13 06:00
PMCR- 2012/01/19
CRDT- 2010/04/27 06:00
PHST- 2009/08/19 00:00 [received]
PHST- 2010/04/02 00:00 [revised]
PHST- 2010/04/09 00:00 [accepted]
PHST- 2010/04/27 06:00 [entrez]
PHST- 2010/04/27 06:00 [pubmed]
PHST- 2010/08/13 06:00 [medline]
PHST- 2012/01/19 00:00 [pmc-release]
AID - S0016-5085(10)00616-5 [pii]
AID - 10.1053/j.gastro.2010.04.043 [doi]
PST - ppublish
SO  - Gastroenterology. 2010 Aug;139(2):574-85. doi: 10.1053/j.gastro.2010.04.043. Epub 
      2010 Apr 21.