Endothelial ROBO4 suppresses PTGS2/COX-2 expression and inflammatory diseases
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA966093 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24392178.fastq.gz | Fastqsanger.gz | |||
| SRR24392179.fastq.gz | Fastqsanger.gz | |||
| SRR24392180.fastq.gz | Fastqsanger.gz | |||
| SRR24392181.fastq.gz | Fastqsanger.gz | |||
| SRR24392182.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 12 |
Similar Datasets
Project description:Endothelial cells control inflammation in inflammatory and infectious diseases through regulating endothelial gene expression and permeability. Roundabout4 (Robo4) is an endothelial-specific protein that stabilizes endothelial cells. Robo4 has been shown to ameliorate mouse inflammatory and severe infectious diseases, such as sepsis and COVID-19 by reducing vascular permeability. Despite this, it remains uncertain whether these are the only mechanisms by which Robo4 ameliorates the diseases. In this study, we carried out an RNA-seq analysis to investigate the genes regulated by Robo4 in endothelial cells stimulated by TNFα and identified gene, prostaglandin-endoperoxide synthase 2 (PTGS2) , which codes for Cycloocygenase-2 (COX-2). Mechanistic analysis revealed that Robo4 curbs COX-2 expression and endothelial hyperpermeability by preventing prolonged Rac1 activation. Analysis of Robo4 interacting protein identified IQ motif containing GTPase activating protein 1 (IQGAP1) that maintains active Rac1. Robo4 enhanced ubiquitination of IQGAP1 with a ubiquitin E3 ligase, TNF receptor-associated factor 7 (TRAF7), to inactivate Rac1. Finally, Robo4 deficiency exacerbates COX-2 -associated inflammatory diseases, including arthritis, edema, and pain in mouse models. Taken together, Robo4 inhibits Rac1 activation by interacting with TRAF7 and IQGAP1, thereby suppressing the endothelial expression of COX-2 and reducing hyperpermeability. Thus, we uncovered further Robo4 capabilities that suppresses COX-2 and inflammatory diseases, as well as their underlying mechanisms, indicating that endothelial Robo4 is a potential therapeutic target for diverse inflammatory diseases.
2024-05-16 | GSE231460 | GEO
Project description:To investigate the role of the COX-2-dependent lung fibroblast program in reprogramming lung myeloid cells, we generated fibroblast-targeted Ptgs2 conditional knockout mice by crossing Pdgfra-Cre mice with Ptgs2flox/flox mice. Then we isolated two primary types of lung resident DCs-CD103+ conventional DC (cDC1) and CD11b+ conventional DC (cDC2), and lung monocytes from WT and Ptgs2 cKO mice by fluorescence-activated cell sorting and performed RNA sequencing.
2022-07-19 | E-MTAB-11888 | biostudies-arrayexpress
Project description:To better understand the role of the COX-2-dependent lung fibroblast program in modulating the lung immune microenvironment, we generated fibroblast-targeted Ptgs2 conditional knockout (cKO) mice by crossing Pdgfra-Cre mice with Ptgs2flox/flox mice. Then we determined how Ptgs2 deficiency in CD140a+ fibroblasts alters the lung immune microenvironment by performing single-cell RNA sequencing on lung CD45+ immune cells from WT and Ptgs2-cKO mice.
2022-07-19 | GSE206449 | GEO
Project description:We tested the hypothesis that increasing matrix stiffness on which normal human lung fibroblasts are grown promotes the expression of a fibrogenic cellular transcriptomic program. Keywords: Human lung fibroblast, matrix stiffness, PTGS2, COX-2, Prostaglandin E2
2010-07-15 | GSE22011 | GEO
Project description:Tumor hypoxia is not a stable phenomenon but cycles between periods of deep hypoxia and reoxygenation. Cyclic hypoxia originates from heterogeneities in red blood cell flux and from the permanent remodelling of the angiogenic vascular network. Endothelial cells lining tumor blood vessels are therefore also influenced by cyclic hypoxia. The gene expression pattern promoted by cyclic hypoxia differs from those observed under normoxia and even continuous hypoxia. PTGS2 is one gene exquisitely up-regulated in endothelial cells (and tumor cells) in response to cyclic hypoxia. Elevated COX-2 (the PTGS2 gene product) expression and activity account for cyclic hypoxia-driven increase in endothelial cell survival and angiogenesis.
2009-12-24 | GSE12246 | GEO
Project description:We tested the hypothesis that increasing matrix stiffness on which normal human lung fibroblasts are grown promotes the expression of a fibrogenic cellular transcriptomic program. Keywords: Human lung fibroblast, matrix stiffness, PTGS2, COX-2, Prostaglandin E2 Total RNA extracted from normal human lung fibroblasts from 3 human subjects and separately grown on 5 discrete matrix stiffness conditions: 100, 400, 1600, 6400, 25600 Pascals.
2010-07-15 | E-GEOD-22011 | biostudies-arrayexpress
Project description:Chromosome 17p deletions are one of the most frequent chromosomal alterations in human cancers and also lymphoma. Although it has been assumed to be equal to p53 loss for a long time, there are emerging evidence suggesting that there would be additional p53–independent mechanisms. Our previous work identified ALOX15B, an arachidonate lipoxygenase, as a 17p tumor suppressor in lymphoma. Interestingly, five of the six ALOX genes locate on this region and frequently co-deleted with TP53. Among them, ALOX15B, ALOX12B and ALOXE3 are adjacent to one another and proximal to the centromere relative to TP53, while ALOX12 and ALOX15 are distal to the centromere relative to TP53. Herein, we show that each of the five 17p ALOX genes repress Myc-driven lymphomagenesis in mice. Mechanistically, deficiency of the ALOX arachidonate metabolism pathway activates the paralleling COX-PGE2 pathway, resulting in increasing PTGS2 expression and PGE2 level. PGE2 prevents apoptosis of pre-B cells and Ptgs2 knockdown extends the latency of Myc;shAlox15b lymphoma in vivo. Further, shAlox15b lymphoma cells are more sensitive to COX-2 inhibitor celecoxib than control lymphoma cells. Importantly, the ALOX-COX metabolism unbalance is also observed in human cancers with del(17p). Taken together, our studies reveal the tumor suppression functions of all of the five ALOX genes on chromosome 17p in lymphoma and an unprecedented arachidonate metabolism unbalance between the ALOX and COX pathways underlying human cancers with 17p deletions.
2022-12-21 | GSE147264 | GEO
Project description:Prostaglandin E2 (PGE2) is a powerful immunomodulator synthesized by the COX2 enzyme, coded by human gene PTGS2. PGE2 is known to possess angiogenic, protumor and immunosuppressive functionality in the microenviornment of oropharyngeal carcinomas (OPC). Differential induction of PTGS2 in infiltrating myeloid-derived immunocytes has been observed with media conditioned by cultured OPC biopsies and OPC-derived cell lines alike. To identify PTGS2-inducing, OPC-derived gene products, we utilized bluk RNA sequencing on 4 OPC-derived cell lines to compare expression profiles of PTGS2-inducing (SCC154, SCC25) with that of PTGS2-non-inducing (2A3, SCC152) cell lines. Interleukin-1α (IL-1α) was among the differentially expressed candidates between cell lines.
2022-10-21 | GSE215973 | GEO
Project description:The unregulated expression of COX-2 in tams is causally related to the occurrence, development and outcome of pancreatic ductal adenocarcinoma. We describe a new basic level of transcriptional control of COX-2 expression. Constructing in vivo and in vitro TAM model lines, we found that CTCF plays a significant role in the chromatin remodeling of pancreatic cancer-related macrophages, and showed that CTCF, which acts as both a transcription factor and an insulator, establishes an open chromatin domain, and Induced the expression of LncRNA PACERR in the upstream promoter region of PTGS2. The newly transcribed LncRNA PACERR binds to the RNA binding region of CTCF to play a cis-regulatory role. The formation of CTCF/LncRNA PACERR complex contributes to the recruitment of EP300 histone acetylation transfer, which increases the global scope of histone acetylation and induces the expression of PTGS2. Our findings reveal that CTCF and LncRNA that was regulated by CTCF at the same position work together to form a complex of CTCF/LncRNA PACERR/EP300 and dock in the PTGS2 promoter region to mediate the unexpected mechanism of PTGS2 expression. And LncRNA PACERR as a new potential target for regulating the malignant progression of pancreatic cancer.
2021-06-30 | GSE169451 | GEO
Project description:Resistance to immunotherapy is one of the biggest problems of current oncotherapeutics. WhileT cell abundance is essential for tumor responsiveness to immunotherapy, factors that define the T cell inflamed tumor microenvironment are not fully understood. We conducted an unbiased approach to identify tumor-intrinsic mechanisms shaping the immune tumor microenvironment(TME), focusing on pancreatic adenocarcinoma because it is refractory to immunotherapy and excludes T cells from the TME. From human tumors, we identified EPHA2 as a candidate tumor intrinsic driver of immunosuppression. Epha2 deletion reversed T cell exclusion and sensitized tumors to immunotherapy. We found that PTGS2, the gene encoding cyclooxygenase-2, lies downstream of EPHA2 signaling through TGF? and is associated with poor patient survival. Ptgs2 deletion reversed T cell exclusion and sensitized tumors to immunotherapy; pharmacological inhibition of PTGS2 was similarly effective. Thus, EPHA2-PTGS2 signaling in tumor cells regulates tumor immune phenotypes; blockade may represent a novel therapeutic avenue for immunotherapy-refractory cancers. Our findings warrant clinical trials testing the effectiveness of therapies combining EPHA2-TGF?-PTGS2 pathway inhibitors with anti-tumor immunotherapy, and may change the treatment of notoriously therapy-resistant pancreatic adenocarcinoma.
| S-EPMC6715369 | biostudies-literature