IRF3 drives replication stress signaling and determines sensitivity to genotoxic agents in triple-negative breast cancer cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE263947 | GEO | 2024/05/01
REPOSITORIES: GEO
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Project description:The activation of RIG-I-like receptor (RLR) signaling in cancer cells is widely recognized as a critical cancer therapy method. The expected mechanism of RLR ligand-mediated cancer therapy involves the promotion of cancer cell death and strong induction of interferon (IFN)-β that affects the tumor microenvironment. We have recently shown that activation of RLR signaling in triple-negative breast cancer cells (TNBC) attenuates TGF-β signaling, which partly contributes to the promotion of cancer cell pyroptosis. However, the consequences of suppression of TGF-β signaling by RLR ligands with respect to IFN-β-mediated tumor suppression are not well characterized. This study showed that cytosolic induction of a typical RLR ligand polyI:C in cancer cells produces significant levels of IFN-β, which inhibits the growth of the surrounding cancer cells. In addition, IFN-β-induced cell cycle arrest in surrounding cancer cells was inhibited by the expression of constitutively active Smad3 (caSmad3). caSmad3 suppresses IFN-β expression through the alleviation of IRF3 binding to the canonical target genes, as suggested by ChIP-seq analysis. Based on these findings, a new facet of the pro-tumorigenic function of TGF-β that suppresses IFN-β expression is suggested when exploiting RLR-mediated cancer treatment in TNBC.
2021-12-16 | GSE178830 | GEO
Project description:The activation of RIG-I-like receptor (RLR) signaling in cancer cells is widely recognized as a critical cancer therapy method. The expected mechanism of RLR ligand-mediated cancer therapy involves the promotion of cancer cell death and strong induction of interferon (IFN)-β that affects the tumor microenvironment. We have recently shown that activation of RLR signaling in triple-negative breast cancer cells (TNBC) attenuates TGF-β signaling, which partly contributes to the promotion of cancer cell pyroptosis. However, the consequences of suppression of TGF-β signaling by RLR ligands with respect to IFN-β-mediated tumor suppression are not well characterized. This study showed that cytosolic induction of a typical RLR ligand polyI:C in cancer cells produces significant levels of IFN-β, which inhibits the growth of the surrounding cancer cells. In addition, IFN-β-induced cell cycle arrest in surrounding cancer cells was inhibited by the expression of constitutively active Smad3 (caSmad3). caSmad3 suppresses IFN-β expression through the alleviation of IRF3 binding to the canonical target genes, as suggested by ChIP-seq analysis. Based on these findings, a new facet of the pro-tumorigenic function of TGF-β that suppresses IFN-β expression is suggested when exploiting RLR-mediated cancer treatment in TNBC.
2021-12-16 | GSE188457 | GEO
Project description:The interferon regulatory factors IRF3 and IRF7 are key players in the regulation of type I and III IFN genes. In this study, we analyzed the role of IRF3 and IRF7 for the host response to influenza A virus infections in Irf3-/-, Irf7-/- and Irf3-/-Irf7-/- knock-out mice.
2016-11-02 | GSE77600 | GEO
Project description:Occurrence of Colorectal cancer（CRC）is relevant with gut microbiota. However, role of IRF3, a key signaling mediator in innate immune sensing, has been barely investigated in CRC. Here, we unexpectedly found that the IRF3 deficient mice are hyper-susceptible to the development of intestinal tumor in AOM/DSS and Apcmin/+ models. Genetic ablation of IRF3 profoundly promotes the proliferation of intestinal epithelial cells via aberrantly activating Wnt signaling. Mechanically, IRF3 in resting state robustly associates with the active β-catenin in the cytoplasm, thus preventing its nuclear translocation and cell proliferation, which can be relieved upon microbe-induced activation of IRF3. In accordance, the survival of CRC is clinically correlated with the expression level of IRF3. Therefore, our study identifies IRF3 as a negative regulator of the Wnt/β-catenin pathway and a potential prognosis marker for Wnt-related tumorigenesis, and describes an intriguing link between gut microbiota and CRC via the IRF3-β-catenin axis.
2020-09-16 | GSE155777 | GEO
Project description:Interferon regulatory factor 3 (IRF3) and type I interferons (IFNs) protect against infections1 and cancer2, but excessive IRF3 activation and type I IFN production cause autoinflammatory conditions such as Aicardi?Goutières syndrome3,4 and STING-associated vasculopathy of infancy (SAVI)3. Myocardial infarction (MI) elicits inflammation5, but the dominant molecular drivers of MI-associated inflammation remain unclear. Here we show that ischemic cell death and uptake of cell debris by macrophages in the heart fuel a fatal response to MI by activating IRF3 and type I IFN production. In mice, single-cell RNA-seq analysis of 4,215 leukocytes isolated from infarcted and non-infarcted hearts showed that MI provokes activation of an IRF3?interferon axis in a distinct population of interferon-inducible cells (IFNICs) that were classified as cardiac macrophages. Mice genetically deficient in cyclic GMP-AMP synthase (cGAS), its adaptor STING, IRF3, or the type I IFN receptor IFNAR exhibited impaired interferon-stimulated gene (ISG) expression and, in the case of mice deficient in IRF3 or IFNAR, improved survival after MI as compared to controls. Interruption of IRF3-dependent signaling resulted in decreased cardiac expression of inflammatory cytokines and chemokines and decreased inflammatory cell infiltration of the heart, as well as in attenuated ventricular dilation and improved cardiac function. Similarly, treatment of mice with an IFNAR-neutralizing antibody after MI ablated the interferon response and improved left ventricular dysfunction and survival. These results identify IRF3 and the type I IFN response as a potential therapeutic target for post-MI cardioprotection.
2017-11-06 | GSE106471 | GEO
Project description:Interferon regulatory factor 3 (IRF3) and type I interferons (IFNs) protect against infections1 and cancer2, but excessive IRF3 activation and type I IFN production cause autoinflammatory conditions such as Aicardi?Goutières syndrome3,4 and STING-associated vasculopathy of infancy (SAVI)3. Myocardial infarction (MI) elicits inflammation5, but the dominant molecular drivers of MI-associated inflammation remain unclear. Here we show that ischemic cell death and uptake of cell debris by macrophages in the heart fuel a fatal response to MI by activating IRF3 and type I IFN production. In mice, single-cell RNA-seq analysis of 4,215 leukocytes isolated from infarcted and non-infarcted hearts showed that MI provokes activation of an IRF3?interferon axis in a distinct population of interferon-inducible cells (IFNICs) that were classified as cardiac macrophages. Mice genetically deficient in cyclic GMP-AMP synthase (cGAS), its adaptor STING, IRF3, or the type I IFN receptor IFNAR exhibited impaired interferon-stimulated gene (ISG) expression and, in the case of mice deficient in IRF3 or IFNAR, improved survival after MI as compared to controls. Interruption of IRF3-dependent signaling resulted in decreased cardiac expression of inflammatory cytokines and chemokines and decreased inflammatory cell infiltration of the heart, as well as in attenuated ventricular dilation and improved cardiac function. Similarly, treatment of mice with an IFNAR-neutralizing antibody after MI ablated the interferon response and improved left ventricular dysfunction and survival. These results identify IRF3 and the type I IFN response as a potential therapeutic target for post-MI cardioprotection.
2017-11-06 | GSE106472 | GEO
Project description:The chronic inflammatory state that accompanies obesity is a major contributor to insulin resistance and other metabolic dysfunction features. Despite recent advances in our understanding of the cellular and secreted factors that promote the inflammatory milieu of obesity, we have much less insight into the transcriptional pathways that drive these processes. While most attention has focused on the canonical inflammatory transcription factor NF-KB, other potentially important factors exist, including members of the interferon regultory factor (IRF) family. Here we show that IRF3 expression is upregulated in the adipocytes of obese mice and humans. TLR3/TLR4 activation induces insulin resistance in adipocytes, which can be prevented by IRF3 knockdown. Furthermore, Irf3KO mice display improved insulin sensitivity, associated with reduced intra-adipose and systemic inflammation in the high-fat fed state, enhanced browning of subcutaneous fat, and increased adipose expression of Glut4. Taken together, our data indicates that IRF3 is a major transcriptional regulator of adipose inflammation to maintain systemic glucose and energy homeostasis. Transcriptional profiling of murine 3T3-L1 adipocytes with altered expression of IRF3. Overexpression or knockdown of IRF3 was achieved by lentivirus transduction for 6 days. 3T3-L1 adipocytes with IRF3 knockdown were further treated in the absence or presence of LPS for 6 days. Samples consist of triplicate replica with appropriate control.
2016-05-31 | E-GEOD-81193 | biostudies-arrayexpress
Project description:Interferon regulatory factors (IRFs) play key roles in the transactivation of antiviral genes at the step downstream of activated pathogen-associated molecular pattern sensors, such as RIG-I-like receptors or Toll-like receptors. Whereas IRF1 and IRF3 are thought to bind similar DNA elements (ISRE and PRD-III, PRD-I) to activate antiviral gene transcription, genome-wide transcriptome profiling of IRF1 versus IRF3 knockouts in an immortalized primary hepatocyte (PH5CH8) cell line infected with hepatitis A virus (HAV) revealed unexpected disparities in their target genes. IRF1 targets include several anti-HAV effector genes that were not previously recognized to have antiviral functions.
2018-06-01 | GSE114916 | GEO
Project description:IRF3 is one of the most critical transcription factor in down stream of pattern recognition receptors (such as toll-like receptor and RIG-I-like receptor) signalling pathway. IRF3 is known to induce the expression of type I IFN gene upon virus infection. To furter examine the role of IRF3 in virus-induced gene expression, we preformed microarray analysis in IRF3-/- peritoneal macrophages infected with VSV, and found that IRF3 suppresses the expression of Il12b gene. Peritoneal macrophages from WT of IRF3-/- B6 mice were infected with VSV(1 M.O.I. ) for 6 hous, and then subjected to microarray analysis.
2012-05-19 | E-GEOD-37855 | biostudies-arrayexpress