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

Man, Si Ming; Zhu, Qifan; Zhu, Liqin; Liu, Zhiping; Karki, Rajendra; Malik, Ankit; Sharma, Deepika; Li, Liyuan; Malireddi, R K Subbarao; Gurung, Prajwal; Neale, Geoffrey; Olsen, Scott R; Carter, Robert A; McGoldrick, Daniel J; Wu, Gang; Finkelstein, David; Vogel, Peter; Gilbertson, Richard J; Kanneganti, Thirumala-Devi.
Cell; 162(1): 45-58, 2015 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-26095253
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.
Selo DaSilva