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Quantitative Transcriptome Analysis of the Stomach Neck Mucosa from Control vs Claudin (CLDN)-18 knockout mice.

ABSTRACT: Purpose: To determine early changes in gene expression that drive gastric cancer development in the landscape of CLDN18 loss using RNAseq. Results: Although claudin-18 is a tight junction protein and should regulate paracellular permeabiity and/or ion flux across the mucosa, we showed this protein is rather a potent tumor suppressor that regulates cellular signaling and differentiation pathways in gastric epithelial cells. Methods: Stomach neck region mRNA profiles of 7-day-old wild-type (WT) and claudin-18 knockout (CLDN18−/−) mice were generated by deep sequencing, in triplicate, using the Illumina HiSeq2000 sequencing system. The resulting sequences were mapped to the Mouse genome (mm10) using STAR aliger and P-values were adjusted using the Benjamini-Hochberg procedure (J R Statist Soc B 1995;57:289-300). Conclusions: Loss of claudin-18 promotes gastric cancer development by modulating the expression program of gastric epithelial cells, including cellular signaling and differentiation pathways that are required for mucosal homeostasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE93774 | GEO | 2017/01/19

SECONDARY ACCESSION(S): PRJNA362346

REPOSITORIES: GEO

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Knockout mice reveal key roles for claudin-18 in alveolar fluid homeostasis.

Project description:Claudin proteins are major constituents of epithelial and endothelial tight junctions (TJ), where they serve as regulators of paracellular permeability to ions and solutes. Claudin-18, a member of the large claudin family, is highly expressed in lung epithelium. To elucidate the role of claudin-18 in alveolar epithelial barrier function and fluid homeostasis, we generated claudin-18 knockout (C18 KO) mice. Increased alveolar fluid clearance (AFC) observed in C18 KO mice may have accounted for absence of lung edema despite increased alveolar solute permeability compared to wild type (WT) controls. Higher AFC in C18 KO mice was associated with higher Na-K-ATPase activity and increased expression of the Na-K-ATPase β1 subunit compared to WT controls. Consistent with in vivo findings, alveolar epithelial cell (AEC) monolayers derived from C18 KO mice exhibited lower transepithelial electrical resistance (RT) accompanied by increased solute and ion permeability without changes in ion selectivity. Expression of claudin-3 and claudin-4 was markedly increased in whole lung and in freshly isolated AEC from C18 KO mice, while claudin-5 was unchanged. In contrast, occludin, another major component of the TJ complex, was significantly decreased in C18 KO lung. Further analysis revealed rearrangements in the F-actin cytoskeleton in C18 KO MAECM. These findings demonstrate a crucial non-redundant role for claudin-18 in regulation of alveolar epithelial tight junction composition and permeability to ions and solutes. Importantly, increased AFC in C18 KO mice identifies additional roles for claudin-18 in alveolar fluid homeostasis beyond its direct contributions to barrier properties of the alveolar epithelium. Animals with a ubiquitous knockout (C18 KO) were obtained by crossing mice harboring a conditional (floxed) allele of claudin-18 (Cldn18F/F) with CMV-cre deleter mice to delete exons 2 and 3 by Cre/loxP recombination.

2014-04-06 | E-GEOD-48443 | biostudies-arrayexpress

Knockout mice reveal key roles for claudin-18 in alveolar fluid homeostasis.

2014-04-06 | GSE48443 | GEO

Claudin-7 knockout by gene targeting

Project description:To investigate the claudin-7 function in vivo, we generated a claudin-7 knockout mouse model by gene targeting through homologous recombination. In this study, we report that Cln7-/- pups show Na+, Cl-, and K+ wasting and chronic dehydration phenotypes. The dramatic increase of aldosterone synthase mRNA level suggests that these mice suffer from mishandling of NaCl and fluid in the distal nephrons. Deletion of claudin-7 invokes several compensatory changes, such as increased renin, serum-glucocorticoid-induced kinase 1 (SGK1), epithelial Na+ channel (ENaCα), Na+-Cl- cotransporter (NCC), as well as aquaporin (AQP) 2 mRNA levels, demonstrating the cross talks between paracellular and transcellular ion transport pathways.

2024-02-27 | GSE256329 | GEO

Claudin-10a deficiency shifts proximal tubular Cl- permeability to cation selectivity via claudin-2 translocation

Project description:The tight junction (TJ) proteins claudin-2 and -10a form paracellular cation and anion channels, respectively, and have both been reported to be expressed in the proximal tubule (PT). However, the physiological role of claudin-10a in the kidney is yet obscure. Mice deficient in claudin-10a were generated and successful knockout was confirmed by Southern Blot, Western Blot and immunofluorescence staining. The functionality of isolated PTs was investigated electrophysiologically. Compensatory regulation was studied by pharmacological intervention, RNA-Seq analysis, Western Blot and immunofluorescence staining.

2021-03-02 | GSE167928 | GEO

Expression of the membrane tetraspanin claudin 18 on cancer cells promotes T lymphocyte infiltration and antitumor immunity in pancreatic cancer

Project description:Tumors weakly infiltrated by T lymphocytes poorly respond to immunotherapy. We aimed to unveil malignancy-associated programs regulating T cell entrance, arrest, and activation in the tumor environment. Differential expression of cell adhesion and tissue architecture programs, particularly the presence of the membrane tetraspanin claudin (CLDN)18 as a signature gene, demarcated immune-infiltrated from immune-depleted mouse pancreatic tumors. In human pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer, CLDN18 expression positively correlated with more differentiated histology and favorable prognosis. CLDN18 on the cell surface promoted accrual of cytotoxic T lymphocytes (CTLs), facilitating direct CTL contacts with tumor cells by driving the mobilization of the adhesion protein ALCAM to the lipid rafts of the tumor cell membrane through actin. This process favored the formation of robust immunological synapses (ISs) between CTLs and CLDN18-positive cancer cells, resulting in increased T cell activation. Our data reveal an immune role for CLDN18 in orchestrating T cell infiltration and shaping the tumor immune contexture.

2024-05-14 | GSE230868 | GEO

Analysis of Claudin 18 deficiency in lung epithelial type 2 cells.

Project description:Constitutive knockdown of Cldn18 in mice showed lung enlargement and increased proliferation of alveolar epithelial type II (AT2) cells. Lung AT2 cells were isolated from wild-type and knockout mice and subjected to microarray analysis. Results provide insight into the role of Cldn18 in controlling organ size and stem progenitor cells.

2018-06-30 | GSE106233 | GEO

Analysis of Claudin 18 deficiency in lung epithelial type 2 cells.

Project description:Analysis of Claudin 18 deficiency in lung epithelial type 2 cells.

| PRJNA415968 | ENA

Claudin-1 as a novel target gene induced in obesity and associated to inflammation, fibrosis and cell differentiation

Project description:T-lymphocytes from visceral and subcutaneous white adipose tissue (vWAT and sWAT, respectively) can have opposing roles in the systemic metabolic changes associated with obesity. However, few studies have focused on this subject. Claudin-1 (CLDN1) is a protein involved canonically in Tight Junctions (TJs) and tissue paracellular permeability. We evaluated the gene expression in T lymphocytes from vWAT and sWAT and in the whole adipose depots.

2024-04-03 | GSE236145 | GEO

Claudin-7 is frequently overexpressed in ovarian cancer and promotes invasion

Project description:Claudins are tight junction proteins that are involved in tight junction formation and function. Previous studies have shown that claudin-7 is frequently upregulated in epithelial ovarian cancer (EOC) along with claudin-3 and claudin-4. Here, we investigate in detail the expression patterns of claudin-7, as well as its possible functions in EOC. Initially a total of 95 ovarian tissue samples (7 normal ovarian tissues, 65 serous carcinomas, 11 clear cell carcinomas, 8 endometrioid carcinomas and 4 mucinous carcinomas) were studied for claudin-7 expression using RT-PCR analysis. The gene for claudin-7, CLDN7, was found to be significantly upregulated in all the tumor tissue samples studied. Similarly, immunohistochemical analysis and western blotting showed that claudin-7 protein was significantly overexpressed in the vast majority of EOCs. Two cell lines(OVCAR-2 and OVCA420) were chosen for microarray based gene expression analysis using small interfering RNA-mediated(SiRNA) knockdown of claudin-7. This treatment led to significant changes in gene expression that was validated by RT-PCR and immunoblotting.

2012-09-19 | GSE26055 | GEO

The Tight Junction Protein Claudin-2 Controls Mucosal Permeability, Immune Tolerance and Colitis in Mice

Project description:The mucosal epithelium plays a key role in regulating immune homeostasis. Dysregulation of epithelial barrier function is associated with mucosal inflammation. Expression of claudin-2, a pore-forming tight junction protein, is highly upregulated during inflammatory bowel disease (IBD) and, due to its association with epithelial permeability, has been postulated to promote inflammation. Furthermore, claudin-2 also regulates colonic epithelial cell proliferation and intestinal nutrient absorption. However, the precise role of claudin-2 in regulating colonic epithelial and immune homeostasis remains unclear. Here, we demonstrate, using Villin-Claudin-2 transgenic (Cl-2TG) mice, that increased colonic claudin-2 expression unexpectedly protects mice against experimentally induced colitis and colitis-associated cancer. Notably, Cl-2TG mice exhibited increased colon length and permeability as compared with wild type (WT) littermates. However, despite their leaky colon, Cl-2TG mice subjected to experimental colitis were immune compromised, with reduced induction of TLR-2, TLR-4, Myd-88 expression and NF-kB and STAT3 activation. Most importantly, colonic macrophages in Cl-2TG mice exhibited an anergic phenotype. Claudin-2 overexpression also increased colonocyte proliferation and provided protection against colitis-induced colonocyte death. Taken together, our findings have revealed a critical role of claudin-2 in regulating colonic homeostasis, suggesting novel therapeutic strategies for inflammatory conditions of the gastrointestinal tract.

2013-09-15 | GSE46006 | GEO

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