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Promoter methylation regulates Helicobacter pylori-stimulated cyclooxygenase-2 expression in gastric epithelial cells.
Cancer Res 2001; 61(6):2399-403CR

Abstract

Cyclooxygenase (COX)-2, the inducible form of the rate-limiting enzyme for prostaglandin synthesis, is up-regulated in gastrointestinal cancers and is a key mediator of epithelial cell growth. Helicobacter pylori is causally linked to gastric cancer. In H. pylori gastritis, COX-2 expression localizes to the subepithelial region, with variable levels in the epithelium. In contrast, in gastric cancer, COX-2 strongly predominates in the epithelium, suggesting that the transition to consistent epithelial COX-2 overexpression may be a critical molecular event in gastric carcinogenesis. Because aberrant promoter methylation inhibits expression of a variety of genes in gastrointestinal cancers, we sought to determine whether methylation of the COX-2 promoter could regulate the response to H. pylori in gastric epithelial cells. We assessed COX-2 expression and promoter methylation status in six gastric epithelial cell lines. In all four of the cell lines that exhibited basal expression of COX-2 and a significant increase in expression in response to H. pylori, the COX-2 promoter was unmethylated, whereas in the two cell lines that did not express COX-2, the COX-2 promoter was methylated. Treatment of COX-2-methylated cells with the demethylating agent 5-azacytidine had a modest effect on COX-2 expression, but when 5-azacytidine-treated cells were subsequently stimulated with H. pylori, there was a significant, 5-10-fold enhancement of both COX-2 mRNA and protein expression and release of the COX-2 product, prostaglandin E2. In contrast, in COX-2-expressing cell lines that were unmethylated at the COX-2 promoter, 5-azacytidine had no effect on H. pylori-stimulated COX-2 expression. These findings suggest that loss of COX-2 methylation may facilitate COX-2 expression and promote gastric carcinogenesis associated with H. pylori infection.

Authors+Show Affiliations

Department of Medicine, University of Maryland School of Medicine and Veterans Affairs Maryland Health Care System, Baltimore 21201, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11289104

Citation

Akhtar, M, et al. "Promoter Methylation Regulates Helicobacter Pylori-stimulated Cyclooxygenase-2 Expression in Gastric Epithelial Cells." Cancer Research, vol. 61, no. 6, 2001, pp. 2399-403.
Akhtar M, Cheng Y, Magno RM, et al. Promoter methylation regulates Helicobacter pylori-stimulated cyclooxygenase-2 expression in gastric epithelial cells. Cancer Res. 2001;61(6):2399-403.
Akhtar, M., Cheng, Y., Magno, R. M., Ashktorab, H., Smoot, D. T., Meltzer, S. J., & Wilson, K. T. (2001). Promoter methylation regulates Helicobacter pylori-stimulated cyclooxygenase-2 expression in gastric epithelial cells. Cancer Research, 61(6), pp. 2399-403.
Akhtar M, et al. Promoter Methylation Regulates Helicobacter Pylori-stimulated Cyclooxygenase-2 Expression in Gastric Epithelial Cells. Cancer Res. 2001 Mar 15;61(6):2399-403. PubMed PMID: 11289104.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Promoter methylation regulates Helicobacter pylori-stimulated cyclooxygenase-2 expression in gastric epithelial cells. AU - Akhtar,M, AU - Cheng,Y, AU - Magno,R M, AU - Ashktorab,H, AU - Smoot,D T, AU - Meltzer,S J, AU - Wilson,K T, PY - 2001/4/6/pubmed PY - 2001/5/1/medline PY - 2001/4/6/entrez SP - 2399 EP - 403 JF - Cancer research JO - Cancer Res. VL - 61 IS - 6 N2 - Cyclooxygenase (COX)-2, the inducible form of the rate-limiting enzyme for prostaglandin synthesis, is up-regulated in gastrointestinal cancers and is a key mediator of epithelial cell growth. Helicobacter pylori is causally linked to gastric cancer. In H. pylori gastritis, COX-2 expression localizes to the subepithelial region, with variable levels in the epithelium. In contrast, in gastric cancer, COX-2 strongly predominates in the epithelium, suggesting that the transition to consistent epithelial COX-2 overexpression may be a critical molecular event in gastric carcinogenesis. Because aberrant promoter methylation inhibits expression of a variety of genes in gastrointestinal cancers, we sought to determine whether methylation of the COX-2 promoter could regulate the response to H. pylori in gastric epithelial cells. We assessed COX-2 expression and promoter methylation status in six gastric epithelial cell lines. In all four of the cell lines that exhibited basal expression of COX-2 and a significant increase in expression in response to H. pylori, the COX-2 promoter was unmethylated, whereas in the two cell lines that did not express COX-2, the COX-2 promoter was methylated. Treatment of COX-2-methylated cells with the demethylating agent 5-azacytidine had a modest effect on COX-2 expression, but when 5-azacytidine-treated cells were subsequently stimulated with H. pylori, there was a significant, 5-10-fold enhancement of both COX-2 mRNA and protein expression and release of the COX-2 product, prostaglandin E2. In contrast, in COX-2-expressing cell lines that were unmethylated at the COX-2 promoter, 5-azacytidine had no effect on H. pylori-stimulated COX-2 expression. These findings suggest that loss of COX-2 methylation may facilitate COX-2 expression and promote gastric carcinogenesis associated with H. pylori infection. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/11289104/Promoter_methylation_regulates_Helicobacter_pylori_stimulated_cyclooxygenase_2_expression_in_gastric_epithelial_cells_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=11289104 DB - PRIME DP - Unbound Medicine ER -