Helicobacter pylori infection and gastrin and cyclooxygenase expression in gastric and colorectal malignancies

Konturek, Stanisław J.; Konturek, Peter C.; Hartwich, A; Hahn, Eckhart G.

doi:10.1016/s0167-0115(00)00173-7

Cited by 49 publications

(34 citation statements)

References 25 publications

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“…Recent reports have demonstrated that hypergastrinemia induced by H. pylori infection is often associated with increased COX-2 expression in gastric and colorectal tissues (12,13); because COX-2 is known to cause tumorigenesis (1), these findings suggest the possibility that COX-2 may mediate gastrin-induced carcinogenesis (12)(13)(14). To evaluate potential mechanistic links between gastrin-dependent signaling pathways and the regulation of COX-2 expression in intestinal epithelial cells, we developed the RIE/CCKBR cell line.…”

Section: Discussionmentioning

confidence: 99%

“…Recent evidence shows that 85% of colorectal cancer patients have H. pylori infection and that these patients consistently overexpress COX-2 in the colonic cancer tissue, but not in normal mucosa, where only COX-1 is detected. These data suggest that H. pylori infection may contribute to colorectal carcinogenesis by enhancing colonic expression of gastrin and COX-2 (12,13). The fact that H. pylori induced hypergastrinemia is associated with increased COX-2 expression in gastric and colonic tissues suggests that gastrin may regulate COX-2 expression, but this possibility has not been confirmed (14).…”

mentioning

confidence: 95%

“…Helicobacter pylori infects Ͼ50% of the world population, results in chronic antral gastritis with prolonged hypergastrinemia, and may play a role in development of gastric cancer (12). Recent evidence shows that 85% of colorectal cancer patients have H. pylori infection and that these patients consistently overexpress COX-2 in the colonic cancer tissue, but not in normal mucosa, where only COX-1 is detected.…”

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confidence: 99%

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Gastrin Stimulates Cyclooxygenase-2 Expression in Intestinal Epithelial Cells through Multiple Signaling Pathways

Guo¹,

Cheng²,

Jin³

et al. 2002

Journal of Biological Chemistry

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Gastrin is a hormone produced by G-cells in the normal gastric antrum. However, colorectal carcinoma cells may aberrantly produce gastrin and exhibit increased expression of cholecystokinin B (CCK-B)/gastrin receptors. Gastrin is trophic for the normal gastric oxyntic mucosa and exerts a growth-promoting action on gastrointestinal malignancy. Thus, gastrin may act as an autocrine/paracrine or endocrine factor in the initiation and progression of colorectal carcinoma. The molecular mechanisms involved have not been elucidated. Hypergastrinemia induced by Helicobacter pylori infection is associated with increased cyclooxygenase-2 (COX-2) expression in gastric and colorectal tissues, suggesting the possibility that gastrin up-regulates COX-2 expression in these tissues; this has not been confirmed. We report here that gastrin significantly increases the expression of COX-2 mRNA and protein, the activity of the COX-2 promoter, and the release of prostaglandin E 2 from a rat intestinal epithelial cell line transfected with the CCK-B receptor. These actions were dependent upon the activation of multiple MAPK signal pathways, including ERK5 kinase; transactivation of the epidermal growth factor receptor; and the increased expression and activities of transcription factors ELK-1, activating transcription factor-2, c-Fos, c-Jun, activator protein-1, and myocyte enhancer factor-2. Thus, our findings identify the signaling pathways coupling the CCK-B receptor with up-regulation of COX-2 expression. This effect may contribute to this hormone-dependent gastrointestinal carcinogenesis, especially in the colon.Cyclooxygenase-2 (COX-2) 1 is an inducible enzyme catalyzing the rate-limiting step in prostaglandin synthesis, converting arachidonic acid to prostaglandin H 2 (1). A large body of genetic and biochemical evidence supports the important role of COX-2 in tumorigenesis, particularly in colorectal cancer (1). COX-2 is overexpressed in cancer cells and is associated with enhanced invasiveness (1). However, the molecular mechanisms leading to up-regulation of COX-2 in intestinal cells are not completely understood.Gastrointestinal hormones regulate gastrointestinal homeostasis by affecting cell proliferation, differentiation, apoptosis, and gene expression. Aberrant control of these biological processes is thought to play an important role in establishment of intestinal neoplasia (2, 3).Gastrin is a gastrointestinal hormone that is produced by G-cells in the normal gastric antrum (4). We (5) and others (6) have shown that expression of cholecystokinin B/gastrin receptors is increased in most colon cancers. Gastrin is trophic for the normal gastric oxyntic mucosa and exerts a growth-promoting action on gastrointestinal malignancy (3,4,7,8). Ciccotosto et al. (9) reported that 69% of colon cancers contain fully processed gastrin and that 100% have detectable amounts of progastrin, reflecting aberrant production of both gastrin and progastrin by colon cancer. Watson et al. (10,11) showed that immune neutralization of gastrin ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 95%

mentioning

confidence: 99%

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Gastrin Stimulates Cyclooxygenase-2 Expression in Intestinal Epithelial Cells through Multiple Signaling Pathways

Guo¹,

Cheng²,

Jin³

et al. 2002

Journal of Biological Chemistry

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“…The main pathogenic mechanism of H. pylori seems to be the activation of the immunoinflammatory response of the host's gastric cells (12,28) , but this stomach infection also helps increase the serum concentration of gastrin (37) . Hypergastrinemia has two main effects: an increase in acid secretion by the parietal cells and a hyperproliferation of the mucosal cells of the gastrointestinal tract (17) . The observation that chronic H. pylori infection promotes hypergastrinemia and that colon neoplasias also develop with an increase of gastrin serum led several authors to evaluate the possible association between the bacteria and the adenomas and adenocarcinomas of the colon.…”

Section: Introductionmentioning

confidence: 99%

Seroprevalence of Helicobacter pylori in patients with colon adenomas in a brazilian university hospital

Buso

Rocha

Diogo

et al. 2009

Arq. Gastroenterol.

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-Context -The association between Helicobacter pylori infection and colon neoplasia has been the subject of recent investigations which have produced controversial results. Objective -To evaluate the prevalence of H. pylori infection in patients with colonic adenomas and also in patients whose colonoscopy exams were normal. Methods -After colonoscopy, the individuals were distributed into two groups: patients with colon adenomas (cases) and patients whose colons were normal (controls). The groups were similar regarding age and gender. The individuals of both groups were subjected to a dosage of IgG antibody against H. pylori. The dosage was applied according to the solid phase, chemiluminescent immunometric assay. The chi-square test was used to analyze the data. Results -There were 30 men and 64 women in each group (94 cases and 94 controls). The mean age of the cases was 59.79 ± 12.25 years and that of the controls was 58.98 ± 11.55 years. The H. pylori serology was positive for 66 (70.21%) of the cases and for 51 (54.25%) of the controls. There was a significant difference (P = 0.024). The odds ratio was 1.98 (CI 95%, 0.82-3.15). The prevalence of H. pylori in cases and controls according to gender, histological type and location of the colon lesions showed a significant difference only among women (P = 0.03), among patients with tubular adenomas (P = 0.03), and in those with distal adenomas (P = 0.038). Conclusion -There is a positive association between H. pylori infection and colonic adenomas. This association is more evident in women, especially for tubular adenomas and distal colonic location. HEADINGS -Helicobacter pylori. Adenoma. Colonic neoplasms. Helicobacter infections.

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“…Studies during the past two decades have demonstrated that the GI peptide hormone gastrin might play key roles in regulating both normal as well as malignant GI growth (Rozengurt and Walsh, 2001). This is of clinical importance since an increase in serum gastrin levels is a common side effect following Helicobacter pylori (H. pylori) infection (Smith et al, 1990;Konturek et al, 2000), or the use of proton pump inhibitors (PPIs) (Lind et al, 1988). Both antral-and tumor-derived gastrin, as well as unprocessed forms (progastrin and glycine-extended gastrin) are capable of stimulating cell proliferation (Seva et al, 1994;Singh et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Gastrin-mediated activation of cyclin D1 transcription involves β-catenin and CREB pathways in gastric cancer cells

et al. 2004

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Gastrin and its precursors promote proliferation in different gastrointestinal cells. Since mature, amidated gastrin (G-17) can induce cyclin D1, we determined whether G-17-mediated induction of cyclin D1 transcription involved Wnt signaling and CRE-binding protein (CREB) pathways. Our studies indicate that G-17 induces protein, mRNA expression and transcription of the G 1 -specific marker cyclin D1, in the gastric adenocarcinoma cell line AGSE (expressing the gastrin/cholecystokinin B receptor). This was associated with an increase in steadystate levels of total and nonphospho b-catenin and its nuclear translocation, indicating the activation of the Wnt-signaling pathway. In addition, G-17-mediated increase in cyclin D1 transcription was significantly attenuated by axin or dominant-negative (dn) T-cell factor 4(TCF4), suggesting crosstalk of G-17 with the Wnt-signaling pathway. Mutational analysis indicated that this effect was mediated through the cyclic AMP response element (CRE) (predominantly) and the TCF sites in the cyclin D1 promoter, which was also inhibited by dnCREB. Furthermore, G-17 stimulation resulted in increased CRE-responsive reporter activity and CREB phosphorylation, indicating an activation of CREB. Chromatin immunoprecipitation studies revealed a G-17-mediated increase in the interaction of b-catenin with cyclin D1 CRE, which was attenuated by dnTCF4 and dnCREB. These results indicate that G-17 induces cyclin D1 transcription, via the activation of b-catenin and CREB pathways.

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Helicobacter pylori infection and gastrin and cyclooxygenase expression in gastric and colorectal malignancies

Cited by 49 publications

References 25 publications

Gastrin Stimulates Cyclooxygenase-2 Expression in Intestinal Epithelial Cells through Multiple Signaling Pathways

Gastrin Stimulates Cyclooxygenase-2 Expression in Intestinal Epithelial Cells through Multiple Signaling Pathways

Seroprevalence of Helicobacter pylori in patients with colon adenomas in a brazilian university hospital

Gastrin-mediated activation of cyclin D1 transcription involves β-catenin and CREB pathways in gastric cancer cells

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