Increased expression of Deleted in Malignant Brain Tumors (DMBT1) gene in advanced precancerous gastric lesions in three ethnic populations: effect of modulation on mouse mucous metaplasia in response to H. pylori infection
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ABSTRACT:
OTHER RELATED OMICS DATASETS IN: GSE83389
PROVIDER: PRJNA325779 | ENA |
REPOSITORIES: ENA
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Project description:Helicobacter pylori infection triggers a cascade of inflammatory stages that may lead to the appearance of non-atrophic gastritis, multifocal atrophic gastritis, intestinal metaplasia, dysplasia, and cancer. Deleted in malignant brain tumors 1 (DMBT1) belongs to the group of secreted scavenger receptor cysteine-rich proteins and is considered to be involved in host defense by binding to pathogens. Recent studies have shown that DMBT1 expression is up-regulated in areas of intestinal metaplasia and in gastric tumors. Here, we examined the role of DMBT1 in the development of inflammatory response and gastric precancerous lesions in Caucasian, African American and Hispanic populations as well as in a mouse model. We found that mucosal DMBT1 expression is significantly increased in individuals with more advanced gastric precancerous lesions. We also show that H. pylori infection of Dmbt1-/- mice results in enhanced gastric inflammation and the development of mucous metaplasia that is accompanied by increased cell proliferative rates and reduced IL-33 expression levels in the inflamed mucosa. Taken together, our data suggest that DMBT1 may be mediating mucosal protection that may reduce the risk of developing gastric precancerous lesions in response to H. pylori infection
2017-06-30 | GSE83389 | GEO
Project description:Gastric cancer continues to be one of the most common cancers, with the third highest cancer-related mortality in the world. After infection with Helicobacter pylori, a cascade of inflammatory events that can lead to gastric cancer is triggered. This inflammatory response to the infection is characterized by the infiltration of mononuclear and polymorphonuclear cells into the infected mucosa. The transition of these cells from the circulation to the tissues is mediated through the interaction of receptors on the immune cells and their ligands in the endothelial compartment. CD44 is the receptor for hyaluronan, but it also interacts with osteopontin and collagen, among other molecules. Previous reports have shown that CD44 expression is increased in advanced gastric lesions. However, the association of this molecule with the progression of these lesions over time has not been investigated. In addition, there is a lack of understanding of the CD44-dependent cellular processes that lead to gastritis, and possibly to gastric cancer. Here we studied a subset of subjects from a cohort of individuals with various degrees of gastric inflammation to determine gene expression changes associated with disease progression over a period of six years. We report that CD44 expression is significantly increased in individuals whose gastric lesions progressed over time (from multifocal atrophic gastritis to intestinal metaplasia or from intestinal metaplasia to dysplasia) along the gastric precancerous cascade. We also show that CD44-/- mice develop less severe and less extensive Helicobacter pylori-induced metaplasia, and show fewer infiltrating Gr1+ cells compared to wild type mice. Thus, we present data suggesting that CD44 is associated with disease progression. Mechanisms associated with these effects include induction of interferon gamma responses.
2015-12-17 | GSE69144 | GEO
Project description:Gastric cancer continues to be one of the most common cancers, with the third highest cancer-related mortality in the world. After infection with Helicobacter pylori, a cascade of inflammatory events that can lead to gastric cancer is triggered. This inflammatory response to the infection is characterized by the infiltration of mononuclear and polymorphonuclear cells into the infected mucosa. The transition of these cells from the circulation to the tissues is mediated through the interaction of receptors on the immune cells and their ligands in the endothelial compartment. CD44 is the receptor for hyaluronan, but it also interacts with osteopontin and collagen, among other molecules. Previous reports have shown that CD44 expression is increased in advanced gastric lesions. However, the association of this molecule with the progression of these lesions over time has not been investigated. In addition, there is a lack of understanding of the CD44-dependent cellular processes that lead to gastritis, and possibly to gastric cancer. Here we studied a subset of subjects from a cohort of individuals with various degrees of gastric inflammation to determine gene expression changes associated with disease progression over a period of six years. We report that CD44 expression is significantly increased in individuals whose gastric lesions progressed over time (from multifocal atrophic gastritis to intestinal metaplasia or from intestinal metaplasia to dysplasia) along the gastric precancerous cascade. We also show that CD44-/- mice develop less severe and less extensive Helicobacter pylori-induced metaplasia, and show fewer infiltrating Gr1+ cells compared to wild type mice. Thus, we present data suggesting that CD44 is associated with disease progression. Mechanisms associated with these effects include induction of interferon gamma responses.
2015-12-17 | GSE69145 | GEO
Project description:Gastric intestinal metaplasia (GIM) is an important precancerous lesion in intestinal-type gastric cancer, with persistent Helicobacter pylori (H. pylori) infection inducing the condition. In a previous study, we identified a new H. pylori virulence factor, SlyD. However, its mode of action between GIM was unknown. Our findings offer clues to reveal the molecular mechanism of H.pylori infection-associated gastric intestinal metaplasia, and provides the mechanism of a novel H. pylori virulence factor SlyD in gastric precancerous disease.
2024-11-26 | GSE282336 | GEO
Project description:Alternatively-activated macrophages (M2) are known to play a critical role in intestinalization of spasmolytic polypeptide-expressing metaplasia (SPEM), which is a precursor to gastric adenocarcinoma. However, the precise mechanism(s) and critical mediators produced by M2 macrophages that lead to SPEM are unknown. Using established murine models of metaplasia in the stomach, the aim of the present study was to determine how M2 macrophages induce intestinalized SPEM. Macrophages from the stomach corpus of mice with SPEM (DMP-777-treated) or advanced intestinalized SPEM (L635-treated) were isolated and RNA sequencing was performed. IL-33 was the most upregulated cytokine in macrophages associated with intestinalized SPEM. L635-treated IL-33 knock out mice did not develop metaplasia, suggesting that IL-33 is required for the induction of SPEM after acute parietal cell loss. While the loss of IL-33 did not reduce macrophage recruitment into the mucosa, infiltrating macrophages were not M2 polarized. We conclude that IL-33 is necessary for both the induction of mucous metaplasia (SPEM) in the stomach and polarization towards M2 in recruited macrophages. Our data suggest that the inflammatory pathway in the stomach after parietal cell loss resembles pathways associated with allergy-induced airway inflammation, which implicates novel treatment options for gastritis patients to prevent gastric cancer.
2017-01-20 | GSE77195 | GEO
Project description: Not available
| S-EPMC8603302 | biostudies-literature
Project description:Background: Intestinal metaplasia (IM) is a gastric precancerous lesion that precedes the development of gastric cancer in up to 3.77 cases/1000 person-years. It consists in a trans-differentiation process of gastric to intestinal tissue. Two histological subtypes exist, complete (CIM) and incomplete (IIM), the latter having higher progression rates to gastric cancer . Our objective was to identify molecular processes responsible for the tumoral transition from intestinal metaplasia to GC and the initial steps of this lesion Methods: We used expression microarray to compare the transcriptome of intestinal metaplasia subtypes that progress to gastric cancer (IIM-GC and CIM-GC) after a follow-up period with respect to those that do not progress (IIM control and CIM control). Also, IM-NoGC (IM control, comprising both IIM and CIM Control) was compared with healthy gastric mucosa. Differentially expressed genes were obtained and functional analyses (GSEA and IPA softwares) were performed. Some deregulated genes were validated by qPCR. Results: Histological subtypes of intestinal metaplasia that progress or not to GC differ less among them than to healthy mucosa. Incomplete intestinal metaplasia has a higher number of over-expressed carcinogenic genes and molecular processes than the complete subtype. Most relevant molecular processes and genes in this group include antigenic processing, inflammation, activation of cell cycle and cell proliferation, oncogenes and tumor suppressors. When IM-NoGC is compared with healthy gastric mucosa new identified transcripts include TRIM, TMEM, homeobox, transporters and nucleolar RNAs SNORDs116. We confirm previously reported processes such us intestinal differentiation, metabolism of lipids and of xenobiotics and identify new ones such as non tumoral Warburg effect and melatonin degradation. Conclusions: Differentially expressed genes and molecular processes have been identified for the first time in intestinal metaplasia that progress to gastric cancer. New genes and molecular processes have also been identified in intestinal metaplasia in comparison with healthy gastric mucosa.
2017-06-12 | GSE78523 | GEO
Project description:Intestinal metaplasia (IM), precancerous lesions of gastric carcinoma (PLGC) induced by factors like nitrite, Helicobacter pylori, or bile acid, carries a high risk of progressing to gastric cancer. IM is categorized into complete intestinal metaplasia (CIM) and incomplete intestinal metaplasia (IIM). Patients with IIM are at a higher risk of developing gastric cancer, emphasizing its importance for early screening. Besides the diagnostic challenges, the mechanisms underlying its progression remain a mystery. OLFM4, a gene associated with stemness characteristics, has been linked to promoting gastric and colorectal cancers. Our investigation used pathological sections from two clinical centers, biopsies of IM tissues, PLGC cell models, animal models, and organoids to explore OLFM4's role in IIM. OLFM4 expression was observed highly in IIM, with superior diagnostic accuracy of IIM compared to CDX2 and MUC2 for the first time. OLFM4, along with MYH9, was highly expressed in IM organoids and PLGC animal models. OLFM4, in combination with MYH9, accelerated the ubiquitination of GSK3β and resulted in increased β-catenin levels through the Wnt signaling pathway, finally promoting the proliferation and invasion abilities of PLGC cells. In conclusion, OLFM4 serves as a novel biomarker for IIM and is utilized as an important auxiliary means to delimit the key population for early gastric cancer screening. This study provides new insights into the mechanisms of progression and a new target of therapy in intestinal metaplasia.
2024-01-01 | GSE251765 | GEO
Project description:The Malaysian Node of the Human Variome Project Database (MyHVPDb) is a country specific database of human variant and gene mutation that was established in 2011. This ethnic specific mutation and variation databases are being continuously updated, recording extensive information over the genetic heterogeneity of the Malaysian ethnic groups. The database comprises of SNP Database and Mutation Database. The SNP database has stored 291718 SNPs that was obtained by genotyping the SNPs of 101 healthy individuals from six Malay sub-ethnic groups which consist of Malay Kelantan, Malay Banjar, Malay Kedah, Malay Jawa, Malay Bugis and Malay Champa.
2015-02-11 | GSE65760 | GEO
Project description:The airways are conduits that transport atmospheric oxygen to the distal alveolus. Normally, airway mucous cells are rare. However, diseases of the airway are often characterized by mucous metaplasia, in which there are dramatic increases in mucous cell numbers. As the Notch pathway is known to regulate cell fate in many contexts, we misexpressed the active intracellular domain of the mouse Notch1 receptor in lung epithelium. Notch misexpression resulted in an increase in mucous cells and a decrease in ciliated cells in the airway. Similarly, mouse embryonic tracheal explants and adult human airway epithelium treated with Notch agonists displayed increased mucous cell numbers and decreased ciliated cell numbers. Notch antagonists had the opposite effect. Notably, Notch antagonists blocked IL13-induced mucous metaplasia. IL13 has a well-established role as an inflammatory mediator of mucous metaplasia and functions through Stat6-mediated gene transcription. We found that Notch ligands, however, are able to cause mucous metaplasia in Stat6-null cultured trachea, thus identifying a novel pathway that stimulates mucous metaplasia. Notch signaling may therefore play an important role in airway disease and, by extension, Notch antagonists may have therapeutic value. Conversely, in the distal lung, Notch misexpression prevented the differentiation of alveolar cell types. Instead, the distal lung formed cysts composed of cells that were devoid of alveolar markers but that expressed some, but not all, markers of proximal airway epithelium. Occasional distal cystic cells appeared to differentiate into normal proximal airway cells, suggesting that ectopic Notch signaling arrests the normal differentiation of distal lung progenitors before they initiate an alveolar program.
| S-EPMC2673763 | biostudies-literature