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

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.

SUBMITTER: Man SM

PROVIDER: S-EPMC4491002 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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

Man Si Ming SM Zhu Qifan Q Zhu Liqin L Liu Zhiping Z Karki Rajendra R Malik Ankit A Sharma Deepika D Li Liyuan L Malireddi R K Subbarao RK Gurung Prajwal P Neale Geoffrey G Olsen Scott R SR Carter Robert A RA McGoldrick Daniel J DJ Wu Gang G Finkelstein David D Vogel Peter P Gilbertson Richard J RJ Kanneganti Thirumala-Devi TD

Cell 20150618 1

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 p ...[more]

PMID: 26095253

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Project description:ObjectivePharmacological activation of adenosine signaling has been shown to increase ?-cell proliferation and thereby ?-cell regeneration in zebrafish and rodent models of diabetes. However, whether adenosine has an endogenous role in regulating ?-cell proliferation is unknown. The objective of this study was to determine whether endogenous adenosine regulates ?-cell proliferation-either in the basal state or states of increased demand for insulin-and to delineate the mechanisms involved.MethodsWe analyzed the effect of pharmacological adenosine agonists on ?-cell proliferation in in vitro cultures of mouse islets and in zebrafish models with ?- or ?-cell ablation. In addition, we performed physiological and histological characterization of wild-type mice and mutant mice with pancreas- or ?-cell-specific deficiency in Adora2a (the gene encoding adenosine receptor A2a). The mutant mice were used for in vivo studies on the role of adenosine in the basal state and during pregnancy (a state of increased demand for insulin), as well as for in vitro studies of cultured islets.ResultsPharmacological adenosine signaling in zebrafish had a stronger effect on ?-cell proliferation during ?-cell regeneration than in the basal state, an effect that was independent of the apoptotic microenvironment of the regeneration model. In mice, deficiency in Adora2a impaired glucose control and diminished compensatory ?-cell proliferation during pregnancy but did not have any overt phenotype in the basal state. Islets isolated from Adora2a-deficient mice had a reduced baseline level of ?-cell proliferation in vitro, consistent with our finding that UK432097, an A2a-specific agonist, promotes the proliferation of mouse ?-cells in vitro.ConclusionsThis is the first study linking endogenously produced adenosine to ?-cell proliferation. Moreover, we show that adenosine signaling via the A2a receptor has an important role in compensatory ?-cell proliferation, a feature that could be harnessed pharmacologically for ?-cell expansion and future therapeutic development for diabetes.

Dataset Information

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

Publications

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

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