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Cell. 2015 Jul 2;162(1):45-58. doi: 10.1016/j.cell.2015.06.001. Epub 2015 Jun 18.

Critical Role for the DNA Sensor AIM2 in Stem Cell Proliferation and Cancer.

Author information

1
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
2
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
3
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
4
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Biochemistry and Molecular Biology, School of Basic Medicines, Gannan Medical University, Ganzhou, Jiangxi 341000, China.
5
Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
6
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
7
Animal Resources Center and the Veterinary Pathology Core, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
8
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
9
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: thirumala-devi.kanneganti@stjude.org.

Abstract

Colorectal cancer is a leading cause of cancer-related deaths. Mutations in the innate immune sensor AIM2 are frequently identified in patients with colorectal cancer, but how AIM2 modulates colonic tumorigenesis is unknown. Here, we found that Aim2-deficient mice were hypersusceptible to colonic tumor development. Production of inflammasome-associated cytokines and other inflammatory mediators was largely intact in Aim2-deficient mice; however, intestinal stem cells were prone to uncontrolled proliferation. Aberrant Wnt signaling expanded a population of tumor-initiating stem cells in the absence of AIM2. Susceptibility of Aim2-deficient mice to colorectal tumorigenesis was enhanced by a dysbiotic gut microbiota, which was reduced by reciprocal exchange of gut microbiota with healthy wild-type mice. These findings uncover a synergy between a specific host genetic factor and gut microbiota in determining the susceptibility to colorectal cancer. Therapeutic modulation of AIM2 expression and microbiota has the potential to prevent colorectal cancer.

Comment in

PMID:
26095253
PMCID:
PMC4491002
DOI:
10.1016/j.cell.2015.06.001
[Indexed for MEDLINE]
Free PMC Article

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