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    Home > Biochemistry News > Biotechnology News > PNAS: cGAS limits the development of colon cancer by protecting the integrity of the intestinal barrier

    PNAS: cGAS limits the development of colon cancer by protecting the integrity of the intestinal barrier

    • Last Update: 2021-06-28
    • Source: Internet
    • Author: User
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    The DNA-sensitive enzyme cyclic guanosine monophosphate-adenosine monophosphate synthase (CGAS) regulates inflammation and immune defense against pathogens and malignant cells
    .
    Although cGAS has been shown to have anti-tumor effects in several mouse models carrying transplanted tumor cell lines, its role in endogenous tissue tumors is still unclear

    .
    Here, the authors found that the deletion of the cGAS gene in mice exacerbated chemically induced colitis and colitis-associated colon cancer (CAC)

    .
    Interestingly, under the same conditions, mice lacking cGAS are more likely to develop CAC than mice lacking interferon gene stimulus (STINT) or type I interferon receptors

    .
    CGAS is highly expressed in intestinal stem cells instead of STING

    .
    In the acute injury induced by sodium dextran sulfate, cGAS deficiency leads to the loss of intestinal stem cells and impaired intestinal barrier integrity

    .
    During the development of CAC, the loss of cGAS aggravated inflammation, led to the activation of STAT3, and accelerated the proliferation of intestinal epithelial cells

    .
    Mice lacking cGAS also accumulate myeloid suppressor cells in the tumor, showing enhanced Th17 differentiation, but decreased production of interleukin (IL)-10

    .
    These results indicate that cGAS plays an important role in the occurrence and development of CAC by protecting the integrity of the intestinal mucosa

    .

    Colorectal cancer is one of the most common malignant tumors and the main cause of cancer deaths in men and women
    .
    Among the many factors in the occurrence and development of colorectal cancer, inflammation is the main risk factor that promotes the occurrence and development of colorectal cancer

    .
    Patients with inflammatory bowel disease (IBD) have an increased risk of colorectal cancer

    .
    Innate immunity is related to maintaining the stability of the gastrointestinal environment and the pathogenesis of IBD and IBD-related colorectal cancer

    .

    Cyclic guanosine monophosphate synthase (cGAS) is a DNA sensor that can trigger innate immune responses
    .
    After CGAS binds to DNA, it catalyzes the synthesis of the second messenger 2'3'-cGAMP, which in turn binds and activates the endoplasmic reticulum resident protein stimulator (STING) of the interferon (IFN) gene

    .
    STING activates Iκb kinase (IKK) and tank-binding kinase 1 (TBK1), causing the transcription factors NF-κB and IRF3 to activate respectively, and then work together to induce the expression of type I ifn and other immunomodulatory molecules

    .
    CGAS is important for the host to resist viral and bacterial infections, but when it is abnormally activated by its own DNA, it can also cause autoimmune diseases

    .
    The CGAS-STING pathway has also been shown to play an important role in tumor growth, inflammation and immune surveillance

    .
    The activation of the endogenous STING pathway of antigen-presenting cells induces spontaneous T cell initiation and anti-tumor immune response

    .
    Intratumoral injection of stimulants, such as cGAMP or other cyclic dinucleotides, can induce the regression of established tumors and produce systemic immune responses and immune memory in mouse models of skin cancer, brain cancer, breast cancer and blood cancer

    .
    The CGAS-STING pathway is also important for the efficacy of traditional and new therapies, including radiotherapy, chemotherapy (such as paclitaxel and PARP inhibitors) and immunotherapy (such as anti-programmed cell death antibody [PD]-1, PD-L1) And CD47)

    .
    CGAS also regulates cell senescence to affect tumor growth and development

    .
    However, the inflammation caused by the cGAS-STING pathway can also promote tumor growth and metastasis

    .

    In this study, the authors used dextran sodium sulfate (Dss)-induced colitis model and colitis-associated colon cancer (Cac) model to study the role of cGAS in colitis
    .
    The authors found in mice that cGAS gene deletion can cause severe colitis and CAC

    .
    Mice lacking cGAS are more susceptible to CAC than mice lacking stinging or type I interferon receptors

    .
    cGAS exhibits a special expression pattern in the colon: the highest expression in intestinal stem cells, and the weakened expression after differentiation

    .
    In contrast, STING is highly expressed in the lamina propria and spleen, but not in the intestinal stem and epithelial cells

    .
    After DSS-induced injury, cGAS knockout but not stinggt/gt mice showed loss of small intestinal stem cells and impaired epithelial barrier

    .
    The cGAS-deficient mice showed elevated inflammatory phenotypes, including enhanced STAT3 activation and an increase in the number of Th17 cells, which together exacerbated colonic inflammation, cell proliferation, and tumorigenesis

    .
    Administration of STAT3 inhibitor or cGAMP can partially inhibit the occurrence of colorectal cancer in cGAS-deficient mice

    .
    These results indicate that cGAS inhibits the occurrence of colitis and tumors by protecting the intestinal mucosal barrier

    .

    The intestinal barrier plays a key role in maintaining the health of the body
    .
    Here, the authors found that the lack of cyclic guanosine monophosphate synthase (CGAS) damages the intestinal epithelial barrier and exacerbates inflammation

    .
    CGAS-deficient mice are highly susceptible to colitis-related colon cancer (CAC), but are not susceptible to sporadic colon cancer

    .
    Surprisingly, the role of cGAS in this process seems to be independent of the type I interferon signal induced by interferon gene stimulus (STINT), because mice lacking STINT or type I interferon receptors are better than those lacking cGAS.
    Mice are less susceptible to CAC

    .
    Intestinal stem cells highly express cGAS instead of STING

    .
    These results indicate that cGAS has a unique role in protecting the intestinal epithelial barrier and preventing the development of colon cancer

    .

    Reference

    Shuiqing Hu et al.
    cGAS restricts colon cancer development by protecting intestinal barrier integrity.
    Proc Natl Acad Sci USA.
    2021 Jun 8;118(23):e2105747118.
    doi: 10.
    1073/pnas.
    2105747118.

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