The effect of myeloid STING knockout after tumor formation on gene expression in AOM/DSS-induced CAC mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE252099 | GEO | 2024/08/14
REPOSITORIES: GEO
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Project description:To better understand the role of sphingolipids in the multifactorial process of inflammatory bowel disease (IBD), we elucidated the role of CerS4 in colitis and colitis-associated cancer (CAC). For this, we utilized the azoxymethane/dextran sodium sulphate (AOM/DSS)-induced colitis model in global CerS4 knockout (CerS4 KO), intestinal epithelial (CerS4 Vil/Cre), or T-cell restricted knockout (CerS4 LCK/Cre) mice. CerS4 KO mice were highly sensitive to the toxic effect of AOM/DSS, leading to a high mortality rate. CerS4 Vil/Cre mice had smaller tumors than WT mice. In contrast, CerS4 LCK/Cre mice frequently suffered from pancolitis and developed more colon tumors. In vitro, CerS4-depleted CD8+ T-cells isolated from the thymi of CerS4 LCK/Cre mice showed impaired proliferation and prolonged cytokine production after stimulation in comparison with T-cells from WT mice. Depletion of CerS4 in human Jurkat T-cells led to a constitutively activated T-cell receptor and NF-κB signaling pathway. In conclusion, the deficiency of CerS4 in T-cells led to an enduring active status of these cells and prevents the resolution of inflammation, leading to a higher tumor burden in the CAC mouse model. In contrast, CerS4 deficiency in epithelial cells resulted in smaller colon tumors and seemed to be beneficial. The higher tumor incidence in CerS4 LCK/Cre mice and the toxic effect of AOM/DSS in CerS4 KO mice exhibited the importance of CerS4 in other tissues and revealed the complexity of general targeting CerS4.
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Project description:Chronic stimulation of innate immune pathways by microbial agents or damaged tissue is known to promote inflammation-driven tumorigenesis by unclarified mechanisms1-3. Here we demonstrate that mutagenic 7,12-dimethylbenz(a)anthracene (DMBA), etoposide or cisplatin induces nuclear DNA leakage into the cytosol to intrinsically activate STING (Stimulator of Interferon Genes) dependent cytokine production. Inflammatory cytokine levels were subsequently augmented in a STING-dependent extrinsic manner by infiltrating phagocytes purging dying cells. Consequently, STING-/- mice, or wild type mice adoptively transferred with STING-/- bone marrow, were almost completely resistant to DMBA-induced skin carcinogenesis compared to their wild type counterparts. Our data emphasizes, for the first time, a role for STING in the induction of cancer, sheds significant insight into the causes of inflammation-driven carcinogenesis, and may provide therapeutic strategies to help prevent malignant disease Total RNA obtained from DMBA or acetone treated wild type (WT) or STING deficient (SKO) mouse skin or skin tumor was examined for gene expression.
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Project description:In response to vascular injury, early EPC or Circulating angiogenic cells (CAC) are thought to be recruited to the damaged areas, participating mainly in a paracrine fashion, by releasing pro-angiogenic factors, promoting the mobilization of other cell populations such as the late EPC, or endothelial colony-forming cells (ECFC). ECFC will help by replacing the damaged endothelium and promoting neovascularization. Unfortunately, however, despite the regenerative role, the number and function of EPC are severely affected under pathological conditions, making compulsory to better understand how these cells react under those environments in order to implement their use in regenerative cell therapies. Herein we evaluated, for the first time to our knowledge, the effect of atherosclerotic factors over the paracrine role of CAC, by direct incubation ex vivo of healthy CAC with the secretome of atherosclerotic arteries. The application of a label free proteomics approach allowed the identification of 194 altered proteins in the secretome of pre-conditioned CAC, many of them related, among others, with inhibition of angiogenesis and cell migration. Functional assays corroborated that, after atherosclerotic pre-conditioning, the pro-angiogenic effect of CAC over ECFC was impaired, affecting ECFC migration as well as their ability to form tubules on a basement membrane matrix assay. Up-regulation of several anti-angiogenic proteins in the CAC secretome could help to explain such angiogenic switch which, in turns, could reflect a protective and beneficial effect against the atherosclerotic process.
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Project description:To find out which miRNAs are significantly differential expression and potentially involved in the process of inflammation promoting carcinogenesis of colorectal cancer (CRC). We established a colitis-associated CRC (AOM/DSS, Azoxymethane/Dextran sulfate sodium salt) model, colitis (DSS) model and high dose carcinogen (AOM, about 5 times AOM amount given than AOM/DSS model) model. At day 100 when tumor formed in AOM/DSS bearing mice (colitis-associated CRC mice) but no tumor was found in AOM (high dose carcinogen) and DSS model, we employed miRNA microarray as a discovery platform to identify genes with the potential to involve in the progression of CRC promoted by inflammation. 5-7 weeks female BALB/c mice, (1) AOM/DSS group: AOM 12.5mg/kg i.p. at day 1, DSS drinking 5d/21dx3circles from day 5; (2) AOM group: AOM 10mg/kg i.p. 1/weekx6 from day 1; (3) DSS group: DSS drinking 5d/21dx3circles from day 5. The distal colon epithelial tissues were collected at day100 when tumor formed in AOM/DSS bearing mice. The miRNA microarray experiments were performed together.
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Project description:Stimulator of Interferon Genes (STING) is a key mediator of type-I interferon (IFN-I) signaling in response to a variety of stimuli, but the contribution of STING to homeostatic processes is not fully characterized. Previous studies showed ligand activation of STING limits osteoclast differentiation in vitro through the induction of IFN and IFN-I Interferon Stimulated Genes (ISGs). In a disease model (SAVI) driven by the V154M gain-of-function mutation in STING, fewer osteoclasts form from SAVI precursors in response to RANKL in an IFN-I-dependent manner. Due to the described role of STING-mediated regulation of osteoclastogenesis in activation settings, we sought to determine whether basal STING signaling contributes to bone homeostasis, an unexplored area. Using whole-body and myeloid-specific deficiency, we show that STING signaling prevents trabecular bone loss in mice over time and that myeloid-restricted STING activity is sufficient for this effect. STING-deficient osteoclast precursors differentiate with greater efficiency than wildtypes. RNA sequencing of wildtype and STING-deficient osteoclast precursor cells and differentiating osteoclasts reveals novel clusters of ISGs including a previously undescribed ISG set expressed in RANKL naïve precursors (tonic expression) and downregulated during differentiation. We identify a 50 gene tonic ISG signature that is STING-dependent and shapes osteoclast differentiation. From this list, we identify Interferon Stimulated Gene 15 (ISG15) as a tonic STING-regulated ISG that limits osteoclast formation. Thus, STING is an important upstream regulator of tonic IFN-I signatures shaping the commitment to osteoclast fates, providing evidence for a nuanced and novel role for this pathway in bone homeostasis.
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