Increased Acid Exposure in Patients With Gastroesophageal Reflux Disease Influences Cyclooxygenase-2 Gene Expression in the Squamous Epithelium of the Lower Esophagus

Abstract

Hypothesis: Although genetic changes associated with the progression to Barrett esophagus and adenocarcinoma have been identified, changes in gene expression associated with gastroesophageal reflux disease have not been reported. We examined expression levels of several genes important in carcinogenesis and compared expression levels with alterations in esophageal acid exposure. Patients, Design, and Setting: Prospective analysis of 61 patients initially seen with reflux symptoms at a private academic hospital. Interventions: Paired esophageal biopsy specimens of squamous epithelium 3 cm above the squamocolumnar junction. All patients had 24-hour pH monitoring performed. Main Outcome Measures: Cyclooxygenase (COX) 1, COX-2, thymidylate synthase, human telomerase reverse transcriptase (hTERT), Bcl-2 protein, survivin protein, secreted protein acidic and rich in cysteine (SPARC), tetraspan (TSPAN), and caudal-type homeobox transcription factor 2 (CDX2) messenger RNA expression analysis was performed on snap-frozen, microdissected tissue using a quantitative reverse transcriptase-polymerase chain reaction method. Linear regression and the Pearson product moment correlation were used to relate gene expression to parameters of the 24-hour pH record. Results: Expression levels of COX-2 correlated positively with the 24-hour pH score (r=0.25, P=.05). There was no correlation between the expression of other tested genes and esophageal acid exposure. There was also no significant increase in COX-2 expression in patients with esophagitis or in those who used nonsteroidal antiinflammatory drugs. Conclusions: To our knowledge, these data provide among the first reported correlation of genetic changes and increased esophageal acid exposure in patients with gastroesophageal reflux symptoms. The changes in gene expression occur before any metaplastic changes in the tissue are apparent, and may in the future be useful in predicting which patients will progress through a metaplasia-dysplasia carcinoma sequence.

The Pathogenesis of Barrett’s Esophagus: Secondary Bile Acids Upregulate Intestinal Differentiation Factor CDX2 Expression in Esophageal Cells

“…3,4,[11][12][13][14] Similarly, CDX2 overexpression was also observed in intestinal metaplastic epithelium in the human stomach. 15 Transfection studies showed that CDX2 was able to induce undifferentiated rat IEC6 cells into the differentiation of goblet cells and absorptive enterocytes.…”

“…2,3 Caudal-related homeobox 2 (CDX2) is a homeobox transcription factor that plays an important role in the early differentiation and maintenance of intestinal epithelium. 4 Immunohistochemical staining studies have recently confirmed that CDX2 protein is overexpressed in human Barrett's epithelium, indicating that this intestinal transcription factor may be an early feature of intestinal metaplasia during the development of BE. 5,6 Ambulatory esophageal studies using both spectrophotometric and aspiration techniques have shown that there is much higher bile acid exposure in the esophagus of BE patients than in non-Barrett's GERD counterparts.…”

Nonsteroidal Anti-inflammatory Drugs and Risk of Esophageal and Gastric Adenocarcinomas in Los Angeles County

“…NSAID use can reduce inflammation by inhibiting COX-2 enzyme production. Overexpression of COX-2 has been found in a range of esophageal conditions, including reflux esophagitis (28), dysplasia (29), Barrett's esophagus (29,30), and esophageal adenocarcinoma (28,29,31). Overexpression of COX-2 and increased prostaglandin secretion have also been found to be involved in the growth and metastasis of gastric cancer (32).…”

Nonsteroidal Anti-inflammatory Drugs and the Esophageal Inflammation-Metaplasia-Adenocarcinoma Sequence

“…Overexpression of IL-1h has been reported in patients with esophagitis, Barrett's esophagus, and esophageal adenocarcinoma (42), and overexpression of TNF-a has been reported in patients with Barrett's esophagus (43). Exposure of the distal esophagus to acid reflux and components of bile reflux has been associated with the activation of COX-2 (44)(45)(46). It has been suggested that there is an increase in COX-2 expression before there is any visible histologic evidence of esophagitis (45).…”

“…Exposure of the distal esophagus to acid reflux and components of bile reflux has been associated with the activation of COX-2 (44)(45)(46). It has been suggested that there is an increase in COX-2 expression before there is any visible histologic evidence of esophagitis (45). Overexpression of COX-2 has been shown in patients with reflux esophagitis, Barrett's esophagus, dysplasia, and esophageal adenocarcinoma (14,44,(47)(48)(49)(50)(51)(52)(53)(54), and expression of COX-2 has been reported to be higher in Barrett's esophagus patients compared with reflux esophagitis patients (47).…”