Involvement of cyclooxygenase-2 in gastric mucosal hypertrophy in gastrin transgenic mice

Kanda, Naoki; Seno, Hiroshi; Kawada, Mayumi; Sawabu, Tateo; Uenoyoma, Yoshito; Nakajima, Toshio; Konda, Yoshitaka; Fukui, Hirokazu; Takeuchi, Toshiyuki; Chiba, Tsutomu

doi:10.1152/ajpgi.00113.2005

Cited by 16 publications

(11 citation statements)

References 42 publications

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“…Importantly, the treatment of already existing mucosal hypertrophy with celecoxib also lead to a significant reduction of the mucosal thickness. The increased levels of PGE 2 in the ACT-GAS mice might directly promote prolonged survival of foveolar cells, possibly through EP 4 receptor signaling [89].…”

Section: In Vivo Modelsmentioning

confidence: 99%

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Cyclooxygenase-2 and Gastric Cancer

Thiel

Mrena

Ristimäki

2011

Cancer Metastasis Rev

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Gastric cancer remains a leading cause of cancer-related deaths worldwide, although its incidence has been steadily declining during recent decades. Expression of cyclooxygenase-2 (COX-2) is elevated in gastric carcinomas and in their precursor lesions. COX-2 expression associates with reduced survival in gastric cancer patients, and it has also been shown to be an independent factor of poor prognosis. Several molecular mechanisms are involved in the regulation of COX-2 expression in gastric cancer cell lines, including signal transduction pathways activated by Helicobacter pylori. In gastric tumor models in vivo the role of COX-2 seems to be predominantly to facilitate tumor promotion and growth.

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Section: In Vivo Modelsmentioning

confidence: 99%

“…The role of COX-2 in hypertrophic gastric mucosa was studied in gastrin transgenic mice [89]. These hypergastrinemic (ACT-GAS) mice develop gastric mucosal hypertrophy that can progress to noninvasive intramucosal adenocarcinoma at later stages (80 weeks old mice).…”

Section: In Vivo Modelsmentioning

confidence: 99%

Cyclooxygenase-2 and Gastric Cancer

Thiel

Mrena

Ristimäki

2011

Cancer Metastasis Rev

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“…12). A number of studies have indicated that, in the setting of gastric ulceration or injury, gastrin can promote ulcer healing and repair (26,37), and overexpression of gastrin in transgenic animals leads to mucosal hyperplasia (20). The physiological actions of gastrin are mediated by the gastrin-CCK B subtype receptors (CCK B R; see Ref.…”

mentioning

confidence: 99%

“…CCK B R has also been implicated in gastric mucosal wound healing, with increased CCK B R expression noted in epithelial cells at the regenerative mucosal ulcer margin (32). To date, a number of downstream target genes of gastrin have been reported, including matrix metalloproteinase 9 (44), plasminogen activator inhibitor 2 (41), tenascin-c, S100A6, myosin light chain kinase (25) and cyclooxygenase-2 (20), and TFF1 (23).…”

mentioning

confidence: 99%

Gastrin regulates the TFF2 promoter through gastrin-responsivecis-acting elements and multiple signaling pathways

Alfred²,

Lim³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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Trefoil family factor 2 (TFF2) is expressed in gastrointestinal epithelial cells where it serves to maintain mucosal integrity and promote epithelial repair. The peptide hormone, gastrin, stimulates acid secretion but also induces proliferation of the acid-secreting mucosa. Because the relationship between these peptides of overlapping function is not understood, we chose to investigate the regulatory effect of gastrin on TFF2 expression. The expression of mRNA and protein of TFF2 was determined by RT-PCR and immunohistochemical staining, respectively. A series of truncated and mutant murine TFF2 promoter constructs was generated. Promoter activity was assessed using dual luciferase reporter assays. Gastrin-responsive DNA-binding sites in the TFF2 promoter were evaluated by electrophoretic mobility shift assay. Gastrin significantly increased the level of endogenous mRNA of TFF2 in the gastrin receptor-expressing AGS-E gastric cancer cell line in a time- and dose-dependent manner. TFF2 protein expression in the gastric fundus was elevated in hypergastrinemic (INS-GAS) transgenic mice and reduced in gastrin-deficient mice. Gastrin treatment increased TFF2 promoter activity through cis-acting regions, containing CCAATA- and GC-rich enhancers. Pretreatment with Y-F476, a gastrin/CCK(B) receptor antagonist, abolished gastrin-dependent promoter activity. Inhibitors of protein kinase C (PKC), mitogen/extracellular signal-regulated kinase (MEK1), and phosphatidylinositol 3-kinase (PI 3-kinase) reduced gastrin-dependent TFF2 promoter activity, whereas an epithelial growth factor receptor (EGFR) inhibitor had no effect. We found that gastrin regulates TFF2 transcription through a GC-rich DNA-binding site and a PKC-, MEK1- and PI 3-kinase-dependent but EGFR-independent pathway. Regulation of TFF2 by gastrin may play a role in the maintenance and repair of the gastrointestinal mucosa.

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“…Transgenic mice overexpressing gastrin develop foveolar hyperplasia and gastric cancer, even in the absence of H. pylori. Foveolar hyperplasia is associated with enhanced expression of cyclooxygenase-2 in gastric mucosa and is significantly reduced, but not entirely prevented, by treatment with celecoxib, a selective cyclooxygenase-2 inhibitor [9].…”

Section: Gastrinmentioning

confidence: 99%

Gastric secretion

Hou¹,

Schubert²

2006

Current Opinion in Gastroenterology

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Purpose of reviewTo summarize the literature over the past year on the regulation of gastric exocrine and endocrine secretion. Recent findingsGastric acid secretion by parietal cells is precisely regulated by overlapping neural, hormonal, and paracrine pathways, both centrally and peripherally. Too much acid can induce gastroduodenal injury. Too little acid can interfere with the absorption of iron, calcium, vitamin B 12 , and certain drugs as well as predispose the patient to enteric infection. A number of peptides implicated in the central control of food intake such as ghrelin, orexin, and leptin are present in the stomach and are capable of modulating acid secretion. The precise mechanisms whereby Helicobacter pylori produces perturbations in acid secretion are not precisely known but appear to involve changes in somatostatin and perhaps ghrelin secretion. Both gastrin and gastrin-receptor knockout mice as well as gastrin-overexpressing and cAMP-overexpressing mice develop gastric atrophy; gastric atrophy is associated with antiparietal cell antibodies and may be a model for autoimmune gastritis. Summary A better understanding of the pathways and mechanisms regulating acid secretion as well as the development of genetically engineered mouse models should lead to new strategies to prevent and treat a variety of gastric disorders, including peptic ulcer disease, neoplasia, and autoimmune gastritis.

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Involvement of cyclooxygenase-2 in gastric mucosal hypertrophy in gastrin transgenic mice

Cited by 16 publications

References 42 publications

Cyclooxygenase-2 and Gastric Cancer

Cyclooxygenase-2 and Gastric Cancer

Gastrin regulates the TFF2 promoter through gastrin-responsivecis-acting elements and multiple signaling pathways

Gastric secretion

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