Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA120031 | ENA |
REPOSITORIES: ENA
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Project description:Full title: Cancer Associated Fibroblasts are activated in incipient neoplasia to orchestrate tumor promoting inflammation in an NF-κB-dependent manner. Cancer Associated Fibroblasts (CAFs) support tumorigenesis by stimulating angiogenesis, cancer cell proliferation, and invasion. We demonstrate that CAFs also mediate tumor-enhancing inflammation. Using a mouse model of squamous skin cancer, we found a pro-inflammatory gene signature in CAFs isolated from dysplastic skin. This signature was also evident in CAFs from skin as well as mammary and pancreatic tumors in mice, and in human cancer. Surprisingly, the inflammatory signature was already activated in CAFs isolated from the incipient hyperplastic stage in multistep tumorigenesis. CAFs from this pathway functioned to promote macrophage recruitment, neovascularization and tumor growth in vivo, activities abolished when NF-κB signaling was inhibited. Additionally, we show that normal dermal fibroblasts can be “educated” by carcinoma cells to express pro-inflammatory genes.
2009-09-02 | GSE17817 | GEO
Project description:Full title: Cancer Associated Fibroblasts are activated in incipient neoplasia to orchestrate tumor promoting inflammation in an NF-κB-dependent manner. Cancer Associated Fibroblasts (CAFs) support tumorigenesis by stimulating angiogenesis, cancer cell proliferation, and invasion. We demonstrate that CAFs also mediate tumor-enhancing inflammation. Using a mouse model of squamous skin cancer, we found a pro-inflammatory gene signature in CAFs isolated from dysplastic skin. This signature was also evident in CAFs from skin as well as mammary and pancreatic tumors in mice, and in human cancer. Surprisingly, the inflammatory signature was already activated in CAFs isolated from the incipient hyperplastic stage in multistep tumorigenesis. CAFs from this pathway functioned to promote macrophage recruitment, neovascularization and tumor growth in vivo, activities abolished when NF-κB signaling was inhibited. Additionally, we show that normal dermal fibroblasts can be âeducatedâ by carcinoma cells to express pro-inflammatory genes. Experiment Overall Design: We performed expression profiling analysis of dermal fibroblasts sorted from dysplastic skin tissue of K14-HPV16 mice, and from age matched non transgenic controls. This array analysis was repeated in triplicate. Amplified RNA was hybridized to the 430 2.0 Affymetrix mouse genome arrays.
2009-09-13 | E-GEOD-17817 | biostudies-arrayexpress
Project description:MTD project_description Inflammation and decreased stem cell function characterize organism aging, yet the relationship between these factors remains incompletely understood. This study shows that aged hematopoietic stem and progenitor cells exhibit increased ground-stage NF-κB activity, which enhances their responsiveness to undergo differentiation and loss of self-renewal in response to inflammation. The study identifies Rad21/cohesin as a critical mediator of NF-κB signals, by increasing chromatin accessibility of inter-/intra-genic and enhancer regions. Rad21/NF-κB are required for normal differentiation, but limit self-renewal of hematopoietic stem cells (HSCs) during aging and inflammation in an NF-κB dependent manner. HSCs from aged mice fail to downregulate Rad21/cohesin and inflammation/differentiation inducing signals in the resolution phase after acute inflammation. and The inhibition of cohesin/NF-κB is sufficient to revert the hypersensitivity of aged HSPCs to inflammation-induced differentiation. During aging, myeloid-biased HSCs with disrupted and naturally occurring reduced expression of Rad21/cohesin are increasingly selected over lymphoid-biased HSCs. Together, Rad21/cohesin mediated NF-κB signaling limits HSPC function during aging and selects for cohesin deficient HSCs with myeloid skewed differentiation.
2018-11-28 | PXD011537 | Pride
Project description:NF-κB has a crucial tumor-suppression role in chemical hepatocarcinogenesis (HCC) by preventing hepatocyte apoptosis-induced compensatory proliferation. However, NF-κB is typically activated in chemical HCC animal models and in ~40% HCC patients, in which its role in tumor progression is largely not known. Here we report that transcription factor Miz1 limits tumor-promoting function of NF-κB independently of its transcriptional activity in chemical HCC. In a murine model, hepatocyte-specific deletion of Miz1 exacerbates HCC progression. Miz1 loss results in a unique sub-group of hepatocytes with upregulated NF-κB activity and pro-inflammatory cytokine production, skewing infiltrating macrophages toward M1-like pro-inflammatory phenotype. Mechanistically, Miz1 sequestrates and prevents IKK-phosphorylation of Metadherin (MTDH), thereby inhibiting NF-κB nuclear translocation and transcription activity. In HCC patient specimens, Miz1 expression is inversely correlated with phosphorylation of RelA and MTDH, and poor prognosis. Thus, Miz1 preventing hepatocytes from promoting infiltrating macrophage M1-like phenotype and inflammation in chemical HCC progression.
2021-07-13 | GSE142868 | GEO
Project description:Breast cancer-associated-fibroblasts (bCAFs) consist of two pro-tumoral populations: inflammatory CAFs (iCAF) releasing pro-inflammatory cytokines, and myofibroblastic CAFs (myCAF) known for their extensive production of extracellular matrix proteins and immunosuppressive features. We have previously shown that targeting the anti-apoptotic protein MCL-1 in primary culture of bCAFs directly derived from human samples reduces their myofibroblastic characteristics linked to actomyosin cytoskeleton disorganization and mitochondrial fragmentation. In this study, we explore the involvement of this protein in phenotypic differentiation and plasticity of bCAFs. Single-cell RNA-sequencing analysis reveals a shift from wound-myCAF to IL-iCAFs phenotype expressing genes involved in inflammation like IL-8, IL-1β, CXCL1, CXCL3, CCL2 and in angiogenesis like VEGF after MCL-1 gene silencing in bCAFs. In vitro, targeting of MCL-1 in bCAFs induces an increase of VEGF secretion associated with enhanced endothelial cell tubulogenesis. In ovo, using chicken chorioallantoic membrane model, we engrafted breast cancer cells and bCAFs to study vascularization. Our data suggest that a low level of MCL-1 expression in bCAF is associated with greater peritumoral vascular density in a VEGF-dependent manner. Furthermore, chemotherapy that downregulated MCL-1 expression in bCAFs is accompanied by the same pro-angiogenic effects. Mechanistically, pharmacological inhibition of MCL-1 promotes mitochondrial outer membrane permeabilization and NF-κB activation in cGAS-STING independent-manner. Blockage of NF-κB activity with an IKKβ inhibitor counteracts VEGF and pro-inflammatory factors transcription induced by MCL-1 inhibition in bCAFs. Our findings highlight a novel role for MCL-1 in regulating the pro-angiogenic properties of bCAFs, and provide new elements for characterizing the different bCAFs subpopulations.
2025-08-14 | PXD058906 | Pride
Project description:Dendritic cells (DCs) orchestrate intestinal inflammation in health and diseases. We found that human IBD was associated with heightened non-canonical NF-κB signaling in intestinal DCs. The non-canonical NF-κB pathway, which induces RelB:p52-mediated immune gene expressions, has been implicated in DC functions and that genetic inactivation of RelB:p52 in DCs alleviated experimental colitis in mice. Here, we aim to investigate the regulation of gene expression by noncanonical Nfkb2 pathway in modulating DC function.
2024-06-11 | GSE249101 | GEO
Project description:The aim of this study was to analyze the host responses to ionizing radiation by nuclear factor-κB (NF-κB) bioluminescence imaging-guided transcriptomic tool. Transgenic mice, carrying the NF-κB-driven luciferase gene, were exposed to a single dose of 8.5 Gy total-body irradiation. In vivo imaging showed that a maximal NF-κB-dependent bioluminescent intensity was observed at 3 h after irradiation and ex vivo imaging showed that liver, intestine, and brain displayed strong NF-κB activations. Microarray analysis of these organs showed that irradiation altered gene expression signatures in an organ-specific manner. Pathway analysis showed that pathways associated with metabolism and immune system were altered primarily in liver and intestine. the upregulation of fatty acid binding protein 4, serum amyloid A2, and serum amyloid A3, which are participated in both inflammation and lipid metabolism, suggesting that irradiation might affect the cross pathways of metabolism and inflammation. Moreover, The upregulation of chemokine (CC-motif) ligand 5, chemokine (CC-motif) ligand 20, and Jagged 1 genes suggested that these genes might contribute to the radiation enteropathy. Male transgenic mice (6 to 8 weeks old) were exposed to a single dose of whole-body X-rays generated at 6 MV (Clinac® 21EX medical linear accelerator, Varian, Palo Alto, CA, USA) and at a dose rate of 4 Gy/min. Mice were imaged at 0 h, 1 h, 3 h, 9 h, 24 h, 48 h, or 72 h, or on 7 d or 14 d after irradiation with 8.5 Gy. RNAs were extracted at 3 h after irradiation.
2012-01-01 | E-GEOD-25208 | biostudies-arrayexpress
Project description:Hypertensive heart failure highlights an urgent need for effective therapeutic strategies. Protein kinases regulate multiple pathways in cardiac pathophysiology and may provide promising therapeutic targets. Here, we identified a Cyclin-dependent kinase, CDK9, promoting inflammation and cardiac remodeling in terminally differentiated cardiomyocytes. Firstly, kinase enrichment analysis and experimental evidence revealed CDK9 phosphorylation at Thr-186 in both human and mouse hypertrophic heart tissues. CDK9 loss of function via T186A mutation in cardiomyocytes attenuated Ang II-induced heart remodeling and NF-κB-mediated inflammation, whereas CDK9 overactivation by T186E mutation induces. This regulatory function of CDK9 in cardiac remodeling is cell cycle-independent. Further studies demonstrate that the kinase domain of CDK9 directly binds to NF-κB P65 protein, which leads to the CDK9/P65 complex nuclear translocation, P65 phosphorylation, and transcription of inflammatory and hypertrophic genes in cardiomyocytes. This process requires CDK9 Thr-186 phosphorylation and Cyclin T1 presence, but is independent on IKKβ and CDK9-RNAPII pathways. Pharmacological inhibition of CDK9 phosphorylation significantly attenuated Ang II-induced cardiac inflammation, remodeling, and dysfunction in mice. Collectively, Ang II-activated CDK9 directly binds to and phosphorylates P65 to drive cardiac inflammation and remodeling. This study identifies CDK9 as a potential target in heart failure therapeutics
2026-06-15 | PXD074496 | Pride
Project description:Hypertensive heart failure highlights an urgent need for effective therapeutic strategies. Protein kinases regulate multiple pathways in cardiac pathophysiology and may provide promising therapeutic targets. Here, we identified a Cyclin-dependent kinase, CDK9, promoting inflammation and cardiac remodeling in terminally differentiated cardiomyocytes. Firstly, kinase enrichment analysis and experimental evidence revealed CDK9 phosphorylation at Thr-186 in both human and mouse hypertrophic heart tissues. CDK9 loss of function via T186A mutation in cardiomyocytes attenuated Ang II-induced heart remodeling and NF-κB-mediated inflammation, whereas CDK9 overactivation by T186E mutation induces. This regulatory function of CDK9 in cardiac remodeling is cell cycle-independent. Further studies demonstrate that the kinase domain of CDK9 directly binds to NF-κB P65 protein, which leads to the CDK9/P65 complex nuclear translocation, P65 phosphorylation, and transcription of inflammatory and hypertrophic genes in cardiomyocytes. This process requires CDK9 Thr-186 phosphorylation and Cyclin T1 presence, but is independent on IKKβ and CDK9-RNAPII pathways. Pharmacological inhibition of CDK9 phosphorylation significantly attenuated Ang II-induced cardiac inflammation, remodeling, and dysfunction in mice. Collectively, Ang II-activated CDK9 directly binds to and phosphorylates P65 to drive cardiac inflammation and remodeling. This study identifies CDK9 as a potential target in heart failure therapeutics
2026-06-15 | PXD074483 | Pride
Project description:Gliomas are among the most invasive and chemo-resistant cancers, making them challenging to treat. Chronic inflammation is one of the key drivers of glioma progression as it promotes the aberrant activation of inflammatory pathways such as NF-κB signalling which drives cancer cell invasion, angiogenesis and tissue remodelling. NF-κB factors typically dimerize with its own family members, but emerging evidence of their promiscuous interactions with other oncogenic factors have been reported to activate the transcription of new target genes and function. Here, we show that non-canonical NF-κB activation directly regulates p52 at the ETS1 promoter to activate its expression. This in turn impacts the genomic and transcriptional landscape of ETS1 in a glioma-specific manner. We further show that enhanced non-canonical NF-κB signalling promotes the co-localization of p52 and ETS1, resulting in the transcriptional activation of non-κB and/or non-ETS glioma-promoting genes. We conclude that p52-induced ETS1 overexpression in glioma cells remodels the genome-wide regulatory network of p52 and ETS1 to transcriptionally drive cancer progression
2023-03-17 | GSE207982 | GEO