Document Detail

Gastrin-induced cyclooxygenase-2 expression in Barrett's carcinogenesis.
MedLine Citation:
PMID:  15269153     Owner:  NLM     Status:  MEDLINE    
PURPOSE: Cyclooxygenase (COX)-2 has been causally implicated in carcinogenesis. The evidence for increased COX-2 in the malignant progression of Barrett's esophagus is contradictory. We hypothesize that COX-2 expression may be causally affected by the gastrin status via the cholecystokinin 2 (CCK(2)) receptor. EXPERIMENTAL DESIGN: COX-2 and prostaglandin E(2) expression were evaluated by Western blotting and enzyme-linked immune assay in samples of squamous esophagus, Barrett's esophagus with varying degrees of dysplasia to adenocarcinoma, and normal duodenum. Differentiation status was evaluated by histopathology and villin expression. A longitudinal case-control study compared COX-2 in patients who progressed to adenocarcinoma with nonprogressors matched for age and length of follow-up. Messenger RNA levels of gastrin and CCK(2) receptor in biopsies and cell lines were evaluated by reverse transcription-PCR, and in vitro gastrin stimulation was conducted with and without inhibitors for CCK(2) (YM022) and COX-2 (NS-398). Cell proliferation was evaluated using minichromosome maintenance protein 2 (Mcm2) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. RESULTS: COX-2 expression is significantly increased in Barrett's esophagus before dysplasia development. Expression is highly variable within Barrett's dysplasia and adenocarcinoma samples independent of differentiation status. In a longitudinal case-control study, the expression levels within patients increased over time, regardless of the degree of malignant progression. Biopsies from nondysplastic Barrett's esophagus expressed increased gastrin mRNA levels compared with other biopsies. Gastrin significantly induced COX-2, prostaglandin E(2), and cell proliferation in biopsies and cell lines. Gastrin-induced proliferation can be inhibited by YM022 and NS-398. CONCLUSIONS: COX-2 is up-regulated early in the Barrett's metaplasia sequence. During carcinogenesis, gastrin is a significant determinant of COX-2 activity levels via the CCK(2) receptor.
Salem I Abdalla; Pierre Lao-Sirieix; Marco R Novelli; Laurence B Lovat; Ian R Sanderson; Rebecca C Fitzgerald
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Publication Detail:
Type:  Comparative Study; Journal Article    
Journal Detail:
Title:  Clinical cancer research : an official journal of the American Association for Cancer Research     Volume:  10     ISSN:  1078-0432     ISO Abbreviation:  Clin. Cancer Res.     Publication Date:  2004 Jul 
Date Detail:
Created Date:  2004-07-22     Completed Date:  2005-01-19     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  9502500     Medline TA:  Clin Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4784-92     Citation Subset:  IM    
Cancer Cell Unit Hutchison/MRC Research Centre, Cambridge, United Kingdom.
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MeSH Terms
Adenocarcinoma / genetics,  metabolism,  pathology
Aged, 80 and over
Barrett Esophagus / genetics,  metabolism,  pathology*
Benzodiazepines / pharmacology
Blotting, Western
Case-Control Studies
Cell Differentiation / genetics
Cell Line, Tumor
Cell Proliferation / drug effects
Cyclooxygenase 1
Cyclooxygenase 2
Cyclooxygenase 2 Inhibitors
Cyclooxygenase Inhibitors / pharmacology
Gastrins / genetics,  metabolism,  pharmacology*
Gene Expression Regulation, Enzymologic / drug effects
Isoenzymes / antagonists & inhibitors,  genetics*,  metabolism
Longitudinal Studies
Membrane Proteins
Middle Aged
Nitrobenzenes / pharmacology
Prostaglandin-Endoperoxide Synthases / genetics*,  metabolism
RNA, Messenger / genetics,  metabolism
Receptor, Cholecystokinin B / antagonists & inhibitors,  genetics,  metabolism
Reverse Transcriptase Polymerase Chain Reaction
Sulfonamides / pharmacology
Tumor Cells, Cultured
Reg. No./Substance:
0/Cyclooxygenase 2 Inhibitors; 0/Cyclooxygenase Inhibitors; 0/Gastrins; 0/Isoenzymes; 0/Membrane Proteins; 0/Nitrobenzenes; 0/RNA, Messenger; 0/Receptor, Cholecystokinin B; 0/Sulfonamides; 123653-11-2/N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; 12794-10-4/Benzodiazepines; 145084-28-2/YM 022; EC 1; EC 2; EC protein, human; EC protein, human; EC Synthases

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