Subtle Protective Roles of Clusterin in Gastric Metaplasia After Acute Oxyntic Atrophy.
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ABSTRACT:
SUBMITTER: Vange P
PROVIDER: S-EPMC6305871 | biostudies-literature | 2019
REPOSITORIES: biostudies-literature
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Subtle Protective Roles of Clusterin in Gastric Metaplasia After Acute Oxyntic Atrophy.
Vange Pål P Bruland Torunn T Munkvold Bjørn B Røyset Elin Synnøve ES Gleave Martin M Bakke Ingunn I
Cellular and molecular gastroenterology and hepatology 20180922 1
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Project description:Persistent H. pylori infection triggers the repair program of the mucosa, such as spasmolytic polypeptide-expressing metaplasia (SPEM). However, the mechanism underlying the initiation of SPEM in gastric tissues by H. pylori remains unclear. Here, an increase in telomerase reverse transcriptase (TERT) protein expression is observed in chief cells upon infection with cagA-positive H. pylori. Tert knockout significantly ameliorated H. pylori-induced SPEM and single-cell RNA sequencing demonstrated that the Wnt/β-Catenin pathway is suppressed in gastric cells with Tert knockout. Mechanism study revealed that CagA elevated TERT abundance by disrupting the interaction between TERT and its novel E3 ligase, SYVN1. Interestingly, Nitazoxanide effectively relieved SPEM via inhibition of the Wnt/β-Catenin signaling in vivo. This results clarified the mechanism underlying which CagA activated the TERT/Wnt/β-Catenin pathway, thus promoting the dedifferentiation of chief cells and the occurrence of SPEM in gastric mucosa. This highlights a molecular basis for targeting CagA-activated Wnt signaling in chief cells for the treatment of gastric precancerous lesions.
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Project description:The stomach corpus epithelium is organized into anatomical units that consist of glands and pits. Mechanisms that control the cellular organization of corpus glands and enable their recovery upon injury are not well understood. R-spondin 3 (RSPO3) is a WNT-signaling enhancer that regulates stem cell behavior in different organs. Here, we investigated the function of RSPO3 in the corpus during homeostasis, upon chief and/or parietal cell loss, and during chronic Helicobacter pylori infection. Using organoid culture and conditional mouse models, we demonstrate that RSPO3 is a critical driver of secretory cell differentiation in the corpus gland toward parietal and chief cells, while its absence promoted pit cell differentiation. Acute loss of chief and parietal cells induced by high dose tamoxifen - or merely the depletion of LGR5+ chief cells - caused an upregulation of RSPO3 expression, which was required for the initiation of a coordinated regenerative response via the activation of yes-associated protein (YAP) signaling. This response enabled a rapid recovery of the injured secretory gland cells. However, in the context of chronic H. pylori infection, the R-spondin-driven regeneration was maintained long term, promoting severe glandular hyperproliferation and the development of premalignant metaplasia.
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Project description:ObjectiveMetaplastic lineages in the oxyntic mucosa of the stomach are critical preneoplastic precursors of gastric cancer. Recent studies have demonstrated that spasmolytic polypeptide-expressing metaplasia (SPEM) in the mouse oxyntic mucosa arises from transdifferentiation of mature gastric chief cells. Other investigations of intestinal progenitor cells have shown that cells demonstrating transcriptional activity for leucine-rich repeat containing G-protein-coupled receptor 5 (Lgr5) in the intestine, colon and gastric antrum function as adult stem cells. We have now investigated whether cells demonstrating Lgr5 transcriptional activity in the oxyntic mucosa of mice might be responsible for development of metaplasia.DesignLgr5-EGFP-IRES-Cre(ERT2/+);Rosa26R mice were used to examine the distribution of Lgr5 transcriptionally active cells in the normal oxyntic mucosa as well as after treatment with DMP-777 or L-635 to induce acute SPEM. Lineage mapping was performed to determine if Lgr5-expressing cells gave rise to SPEM.ResultsCells expressing transcriptional activity for Lgr5 in the oxyntic mucosa were present as scattered rare cells only along the lesser curvature of the stomach. These cells also stained for markers of chief cells (intrinsic factor and pepsinogen) but never showed any staining for proliferative markers (Ki-67). In Lgr5-EGFP-IRES-Cre(ERT2/+);Rosa26R mice induced with tamoxifen, treatment with either DMP-777 or L-635 to induce acute oxyntic atrophy caused induction of SPEM, but no lineage mapping into SPEM from Lgr5-expressing cells was observed.ConclusionThe results indicate that, while chief cells with Lgr5 transcriptional activity are present along the lesser curvature of the gastric oxyntic mucosa, they are not responsible for production of metaplasia.
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Project description: Not available
| S-EPMC8357589 | biostudies-literature
Project description:The cytoprotective protein clusterin is often dysregulated during tumorigenesis, and in the stomach, upregulation of clusterin marks emergence of the oxyntic atrophy (loss of acid-producing parietal cells)-associated spasmolytic polypeptide-expressing metaplasia (SPEM). The hormone gastrin is important for normal function and maturation of the gastric oxyntic mucosa and hypergastrinemia might be involved in gastric carcinogenesis. Gastrin induces expression of clusterin in adenocarcinoma cells. In the present study, we examined the expression patterns and gastrin-mediated regulation of clusterin in gastric tissue from: humans; rats treated with proton pump (H+/K+-ATPase) inhibitors and/or a gastrin receptor (CCK2R) antagonist; H+/K+-ATPase β-subunit knockout (H/K-β KO) mice; and Mongolian gerbils infected with Helicobacter pylori and given a CCK2R antagonist. Biological function of secretory clusterin was studied in human gastric cancer cells. Clusterin was highly expressed in neuroendocrine cells in normal oxyntic mucosa of humans and rodents. In response to hypergastrinemia, expression of clusterin increased significantly and its localization shifted to basal groups of proliferative cells in the mucous neck cell-chief cell lineage in all animal models. That shift was partially inhibited by antagonizing the CCK2R in rats and gerbils. The oxyntic mucosa of H/K-β KO mice contained areas with clusterin-positive mucous cells resembling SPEM. In gastric adenocarcinomas, clusterin mRNA expression was higher in diffuse tumors containing signet ring cells compared with diffuse tumors without signet ring cells, and clusterin seemed to be secreted by tumor cells. In gastric cancer cell lines, gastrin increased secretion of clusterin, and both gastrin and secretory clusterin promoted survival after starvation- and chemotherapy-induced stress. Overall, our results indicate that clusterin is overexpressed in hypergastrinemic rodent models of oxyntic preneoplasia and stimulates gastric cancer cell survival.
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Project description:BackgroundGastric cancer (GC) has a poor prognosis with wide variation in survival rates across the world. Several studies have shown premalignant lesions gastric atrophy (GA) and intestinal metaplasia (IM) influence gastric cancer risk. This systematic review examines all available evidence of the risk of GC in patients with GA or IM and explores the geographical variation between countries.MethodsEMBASE, MEDLINE, Web of Science and the Cochrane Library were searched for relevant articles published to June 2016 investigating the risk of GC in individuals with GA or IM. Analysis was performed to determine variation based on geographical location. Study quality was assessed using the Newcastle-Ottawa Scale and heterogeneity between studies was also evaluated.ResultsFifteen relevant articles were identified, in which there were eight studies of GC incidence in GA and nine in IM cohorts (two articles investigated both GA and IM). The incidence rate of GC in patients with GA ranged from 0.53 to 15.24 per 1000 person years, whereas there was more variation in GC incidence in patients with IM (0.38 to 17.08 per 1000 person years). The greatest GC incidence rates were in Asian countries, for patients with GA, and the USA for those with IM (15.24 and 17.08 per 1000 person years, respectively). The largest studies (four over 25,000 person years) had an incidence rate range of 1.0-2.5 per 1000 person years, however, in general, study quality was poor and there was marked heterogeneity.ConclusionOverall there is a wide variation in annual incidence rate of GC from premalignant lesions. With the recent introduction of surveillance guidelines for gastric atrophy and intestinal metaplasia in the Western world, future assessment of this risk should be performed. Furthermore, substantial heterogeneity supports the need for more robust studies in order to pool results and determine the overall incidence rate of gastric cancer for patients with these premalignant lesions.
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Project description:AimIntestinal metaplasia (IM) and gastric atrophy (GA) are precancerous lesions in the stomach. There is a large debate on natural course of these lesions and surveillance strategy in these patients. This meta-analysis was aimed to find the most appropriate follow up and the rate of progression from IM and GA to GC.MethodsThis meta-analysis is followed and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Electronic databases including EMBASE, PubMed, Web of Science databases, Scopus, and the Cochrane Library were searched until July 2018. Cochran's Q test and I-square (I2) test were used to examine heterogeneity across included studies. We pooled data using random-effect or fixed effect models indicated as incidence rate or proportion with 95% confidence intervals (CI). The variables of study included demographic data, endoscopy interval, follow up interval and time, GA and IM type and GC stage. Moreover, incidence rate of GC and progress rate, regress and persistence proportion in both GA and IM patients were assessed.ResultsOverall, 68 original articles out of 32981 citations were included in our meta-analysis. The pooled GC incidence rate in patients with GA was 1.24 (95% CI, 0.80, 1.76; I2: 83.6%) cases per 1,000 person-years. The rates of later diagnosis of IM and gastric dysplasia in patients with GA were estimated as 41.42 (95% CI, 3.11, 64.45; I2: 95.6%) and 6.23 (95% CI, 2.34, 11.46; I2: 83.0%) cases per 1,000 person-years, respectively. The pooled regressed proportion was 32.23 (95% CI, 18.07-48.02; I2: 94.0%) and the persistence proportion was 38.83 (95% CI, 20.20-59.13; I2: 97.0%) per 100 observations in GA patients. In IM studies, the pooled incidence rate of GC was 3.38 (95% CI, 2.13, 4.85; I2: 93.4%) cases per 1,000 person-years. The progressed rate to dysplasia in IM patient was estimated to be 12.51 (95% CI, 5.45, 22.03; I2: 95.1%) cases per 1,000 person-years. The pooled regressed proportion was 31.83 (95% CI, 25.48-38.51; I2: 91.0%) and the persistence proportion was 43.46 (95% CI, 32.52-54.71; I2: 96.0%) per 100 observations in IM patients.ConclusionOverall, the incidence of GC in patients with IM and GA are low but there is heterogeneity in data with the highest rate in Asian, males with those with incomplete IM. There is probability of regression or persistence without progression in patients with IM and GA who receive appropriate management.
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Project description:Background & Aims: The association between chronic inflammation and gastric carcinogenesis is well established, but it is not clear how immune cells and cytokines regulate this process. We investigated the role of interleukin 27 (IL27) in the development of gastric atrophy, hyperplasia, and metaplasia (preneoplastic lesions associated with inflammation-induced gastric cancer) in mice with autoimmune gastritis. Methods: We performed studies with TxA23 mice (control mice), which express a T-cell receptor against the H+/K+ adenosine triphosphatase α chain and develop autoimmune gastritis, and TxA23xEbi3-/- mice, which develop gastritis but do not express IL27. In some experiments, mice were given high-dose tamoxifen to induce parietal cell atrophy and spasmolytic polypeptide-expressing metaplasia (SPEM). Recombinant IL27 was administered to mice with mini osmotic pumps. Stomachs were collected and analyzed by histopathology and immunofluorescence; we used flow cytometry to measure IL27 and identify immune cells that secrete IL27 in the gastric mucosa. Single-cell RNA sequencing was performed on immune cells that infiltrated stomach tissues. Results: We identified IL27-secreting macrophages and dendritic cell in the corpus of mice with chronic gastritis (TxA23 mice). Mice deficient in IL27 developed more severe gastritis, atrophy, and SPEM than control mice. Administration of recombinant IL27 significantly reduced the severity of inflammation, atrophy, and SPEM in mice with gastritis. Single-cell RNA sequencing showed that IL27 acted almost exclusively on stomach-infiltrating CD4+ T cells to suppress expression of inflammatory genes. Conclusions: In studies of mice with autoimmune gastritis, we found that IL27 is an inhibitor of gastritis and SPEM, suppressing CD4+ T-cell–mediated inflammation in the gastric mucosa.
2024-10-01 | GSE278552 | GEO
Project description:BACKGROUND & AIMS:Loss of gastric parietal cells is a critical precursor to gastric metaplasia and neoplasia. However, the origin of metaplasia remains obscure. Acute parietal cell loss in gastrin-deficient mice treated with DMP-777 leads to the rapid emergence of spasmolytic polypeptide/trefoil factor family 2 (TFF2)-expressing metaplasia (SPEM) from the bases of fundic glands. We now sought to characterize more definitively the pathway for emergence of SPEM. METHODS:Emerging SPEM lineages in gastrin-deficient mice treated with DMP-777 were examined for immunolocalization of TFF2, intrinsic factor, and Mist1, and morphologically with electron microscopy. Emerging SPEM was isolated with laser-capture microdissection and RNA was analyzed using gene microarrays. Immunohistochemistry in mouse and human samples was used to confirm up-regulated transcripts. RESULTS:DMP-777-induced SPEM was immunoreactive for TFF2 and the differentiated chief cell markers, Mist1 and intrinsic factor, suggesting that SPEM derived from transdifferentiation of chief cells. Microarray analysis of microdissected SPEM lineages induced by DMP-777 showed up-regulation of transcripts associated with G1/S cell-cycle transition including minichromosome maintenance deficient proteins, as well as a number of secreted factors, including human epididymis 4 (HE4). HE4, which was absent in the normal stomach, was expressed in SPEM of human and mouse and in intestinal metaplasia and gastric cancer in human beings. CONCLUSIONS:Although traditionally metaplasia was thought to originate from normal mucosal progenitor cells, these studies indicate that SPEM evolves through either transdifferentiation of chief cells or activation of a basal cryptic progenitor. In addition, induction of metaplasia elicits the expression of secreted factors, such as HE4, relevant to gastric preneoplasia.
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Project description:Gastric cancer (GC) remains one of the most common causes of mortality worldwide. Intestinal metaplasia (IM) is one of the preneoplastic gastric lesions and is considered an essential predisposing factor in GC development. Here we present a review of recent most relevant papers to summarize major findings on the molecular alterations in gastric IM. The latest progress in novel diagnostic methods allows scientists to identify various types of molecular alterations in IM, such as polymorphisms in various genes, changes in the expression of micro-RNAs and long noncoding RNAs, and altered microbiome profiles. The results have shown that some of these alterations have strong associations with IM and a potential to be used for screening, treatment, and prognostic purposes; however, one of the most important limiting factors is the inhomogeneity of the studies. Therefore, further large-scale studies and clinical trials with standardized methods designed by multicenter consortiums are needed. As of today, various molecular alterations in IM could become a part of personalized medicine in the near future, which would help us deliver a personalized approach for each patient and identify those at risk of progression to GC.
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