Cell-cycle and cancer-associated gene networks activated by Dsg2: evidence of cystatin A deregulation and a potential role in cell
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE62814 | GEO | 2014/10/30
SECONDARY ACCESSION(S): PRJNA265210
REPOSITORIES: GEO
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Project description:Cystatin A (gene: CSTA), is up-regulated in non-small-cell lung cancer (NSCLC) and dysplastic vs normal human bronchial epithelium. In the context that chronic obstructive pulmonary disease (COPD), a small airway epithelium (SAE) disorder, is independently associated with NSCLC (especially squamous cell carcinoma, SCC), but only occurs in a subset of smokers, we hypothesized that genetic variation, smoking and COPD modulate CSTA gene expression levels in SAE, with further up-regulation in SCC. Gene expression was assessed by microarray in SAE of 178 individuals [healthy nonsmokers (n=60), healthy smokers (n=82), and COPD smokers (n=36)], with corresponding large airway epithelium (LAE) data in a subset (n=52). Blood DNA was genotyped by SNP microarray. Twelve SNPs upstream of the CSTA gene were all significantly associated with CSTA SAE gene expression (p<0.04 to 5 x 10-4). CSTA gene expression levels in SAE were higher in COPD smokers (28.4 ± 2.0) than healthy smokers (19.9 ± 1.4, p<10-3), who in turn had higher levels than nonsmokers (16.1 ± 1.1, p<0.04). CSTA LAE gene expression was also smoking-responsive (p<10-3). Using comparable publicly available NSCLC expression data, CSTA was up-regulated in SCC vs LAE (p<10-2) and down-regulated in adenocarcinoma vs SAE (p<10-7). All phenotypes were associated with significantly different proportional gene expression of CSTA to cathepsins. The data demonstrate that regulation of CSTA expression in human airway epithelium is influenced by genetic variability, smoking, and COPD, and is further up-regulated in SCC, all of which should be taken into account when considering the role of CSTA in NSCLC pathogenesis.
2012-06-20 | GSE22047 | GEO
Project description:Cystatin A (gene: CSTA), is up-regulated in non-small-cell lung cancer (NSCLC) and dysplastic vs normal human bronchial epithelium. In the context that chronic obstructive pulmonary disease (COPD), a small airway epithelium (SAE) disorder, is independently associated with NSCLC (especially squamous cell carcinoma, SCC), but only occurs in a subset of smokers, we hypothesized that genetic variation, smoking and COPD modulate CSTA gene expression levels in SAE, with further up-regulation in SCC. Gene expression was assessed by microarray in SAE of 178 individuals [healthy nonsmokers (n=60), healthy smokers (n=82), and COPD smokers (n=36)], with corresponding large airway epithelium (LAE) data in a subset (n=52). Blood DNA was genotyped by SNP microarray. Twelve SNPs upstream of the CSTA gene were all significantly associated with CSTA SAE gene expression (p<0.04 to 5 x 10-4). CSTA gene expression levels in SAE were higher in COPD smokers (28.4 ± 2.0) than healthy smokers (19.9 ± 1.4, p<10-3), who in turn had higher levels than nonsmokers (16.1 ± 1.1, p<0.04). CSTA LAE gene expression was also smoking-responsive (p<10-3). Using comparable publicly available NSCLC expression data, CSTA was up-regulated in SCC vs LAE (p<10-2) and down-regulated in adenocarcinoma vs SAE (p<10-7). All phenotypes were associated with significantly different proportional gene expression of CSTA to cathepsins. The data demonstrate that regulation of CSTA expression in human airway epithelium is influenced by genetic variability, smoking, and COPD, and is further up-regulated in SCC, all of which should be taken into account when considering the role of CSTA in NSCLC pathogenesis. CSTA gene expression was assessed in the small airway epithelium obtained by bronchoscopy from 178 individuals, including healthy nonsmokers (n= 60) and healthy smokers (n= 118) and the large airway epithelium from healthy nonsmokers (n=21) and healthy smokers(n=31). *** Processed data not provided for all gene expression records. *** Blood DNA from the majority of these individuals was genotyped and an association analysis of gene expression with genotypes of all 48 SNPs within 100 kb of CSTA was performed in PLINK, and tested for significance following 103 permutations within ancestral clusters. Supplementary file (linked below) reports genotypes of all 48 SNPs within 100 kb of the CSTA gene for the 112 genotyping Samples.
2012-06-19 | E-GEOD-22047 | biostudies-arrayexpress
Project description:We studied how loss of the desmosome associated protein, desmoglein-2 (Dsg2), in the heart leads to Arrhythmogenic Cardiomyopathy with particular interest in the early stages of disease progression. Mice expressing the cardiac αMHC-Cre promoter were crossed with Dsg2 floxed mice in which exon 4-5 of the Dsg2 gene was flanked by loxP sites, resulting in Cre-mediated excision of Dsg2 in cardiac myocytes. Wild type Dsg2+/+ (Cre-, Dsg2flx/flx) and knockout Dsg2-/- (Cre+, Dsg2flx/flx) mice were generated. RNA-seq was performed on heart tissue obtained from wild-type and Dsg2-/- mice at 2-weeks and 10-weeks of age.
2021-07-22 | GSE153124 | GEO
Project description:Transcriptomic analysis of DSG2-W2A mouse heart tissue. In DSG2-W2A mice, adhesion of the desmosomal molecule desmoglein-2 (DSG2) is abrogated via mutation of its’ major interaction mechanism (so-called "tryptophan swap" (Harrison, Brasch et al. 2016)). Adult DSG2-W2A mut/mut mice resemble the phenotype of Arrhythmogenic Cardiomyopathy (ACM or ARVC) with biventricular fibrosis, impaired systolic output function and arrhythmia. This phenotype was present in mutant mice analysed at the age of 9 weeks compared to 5-days old hearts, which showed no morphological alterations.
2022-12-05 | GSE181868 | GEO
Project description:Desmogleins are transmembrane cadherin proteins and obligate members of the desmosome, a cell-cell adhesion complex which connects adjacent cells and provides structural integrity to tissues. While Desmogleins are well-known for their importance in maintenance of cell-cell junctions, several studies have also highlighted their role in signaling crosstalk with cell-matrix adhesions and the extracellular matrix (ECM). We have recently shown that Desmoglein-2 (Dsg2) controls cell spreading on ECM substrates (fibronectin and collagen) and phosphorylation of focal adhesion proteins via Rap1 GTPase signaling. In our current study, we show that loss of Dsg2 in keratinocytes enhances the expression of ECM proteins and matrix metalloproteinases (MMPs), an effect that was not recapitulated upon loss of Desmocollin-2 (Dsc2) or loss of Dsg2 in other epithelial cell types. Signaling pathways well-known to control ECM function (TGF-B and Rho) were shown to have no effect on Dsg2-mediated changes in ECM and MMP gene expression, but an analysis of global transcriptome changes by RNA sequencing identified major changes in NF-kappaB (NF-KB)-mediated signaling in Dsg2-deficient cells. Interestingly, NF-KB (RelA) activation is elevated in Dsg2-deficient cells, and knockdown of RelA rescued both the enhanced expression of ECM/MMP genes and the enhanced migratory ability of Dsg2-deficient cells. Taken together, this study has identified an important link between Dsg2 and NF-KB signaling involved in controlling matrix production and remodeling, which has relevance for multiple processes in the epidermis such as wound healing and psoriasis.
2025-08-20 | GSE303980 | GEO
Project description: Not available
| S-EPMC4364902 | biostudies-literature
Project description:Microbacterium sp. T-DSG2 Genome sequencing
| PRJNA1446185 | ENA
Project description:In current study, we have established a combined strategy using proximity labeling and genetic screening to identify the cellular ligands of Siglec-9. Our use of proximity labeling using APEX2 fusion proteins followed by quantitative proteomics allowed us to efficiently label and enrich cell surface protein ligands that directly interact with Siglec-9 via sialic acid moieties. By combining with CRISPR knockout screening, we were able to identify functionally significant ligands. We confirmed at the cellular level that DSG2 expressed on cell surfaces directly interacts with Siglec-9, and this interaction is mediated by site-specific N-glycans on the ECD of DGS2. We also demonstrated the binding between DSG2 on A375 melanoma cells and Siglec-9 on macrophages contributes significantly to Siglec-9 signaling and blocking the DSG2-Siglec-9 axis by either DSG2 knockdown or anti-Siglec-9 antibody, releases immune-suppression and increases phagocytosis. Our findings revealed an important ligand in cancer cells for the immunosuppressive receptor Siglec-9, and suggest the potential of disrupting DSG2-Siglec-9 signaling axis in anti-cancer therapy.
2024-12-23 | PXD051557 | Pride
Project description:Background: Cystatin F is a secreted lysosomal cysteine protease inhibitor that has been implicated in affecting the severity of demyelination and enhancing remyelination in pre-clinical models of immune-mediated demyelination. How cystatin F impacts neurologic disease severity following viral infection of the central nervous system (CNS) has not been well characterized and was the focus of this study. We used cystatin F null-mutant mice (Cst7-/-) with a well-established model of murine coronavirus-induced neurologic disease to evaluate the contributions of cystatin F in host defense, demyelination and remyelination. Methods: Wildtype controls and Cst7-/- mice were intracranially (i.c.) infected with a sublethal dose of the neurotropic JHM strain of mouse hepatitis virus (JHMV), with disease progression and survival monitored daily. Immune cell infiltration into the brain and spinal cord was determined by flow cytometry. Spinal cord demyelination was determined by luxol fast blue (LFB) and Hematoxylin/Eosin (H&E) staining and remyelination evaluated by electron microscopy (EM) and calculation of g-ratios. Immune cell infiltration into the CNS and microglia activation were determined by flow cytometry and 10X genomics chromium 3’ single cell RNA sequencing (scRNAseq). Results: JHMV-infected Cst7-/- mice were able to control viral replication within the CNS, indicating that cystatin F is not essential for an effective Th1 anti-viral immune response. Infiltration of T cells and monocytes/macrophages into the spinal cords of JHMV-infected Cst7-/- mice was increased compared to infected controls, and this correlated with amplified demyelination and impaired remyelination. Single-cell RNA-seq of CD45+ cells enriched from spinal cords of infected Cst7-/- and control mice at day 21 post-infection (p.i.) revealed enhanced expression of transcripts encoding macrophage chemoattractant, Ccl2, and T cell chemoattractants, Cxcl9 and Cxcl10, combined with elevated expression of interferon-g (Ifng) transcripts and activation markers in CD8+ T cells from Cst7-/- mice compared to controls. Conclusions: Cystatin F is not required for immune-mediated control of JHMV replication within the CNS. However, JHMV-infected Cst7-/- mice exhibited more severe clinical disease associated with increased demyelination and impaired remyelination. The increase in disease severity was associated with elevated expression of macrophage and T cell chemoattractant chemokines, concurrent with increased neuroinflammation. These findings support the theory that one mechanism by which cystatin F affects chronic disease in mice persistently infected with JHMV is through regulating expression of pro-inflammatory molecules that impact neuroinflammation and neurologic disease.
2024-10-07 | GSE244656 | GEO