Prostaglandin EP2 Receptor Expression is Increased in Barrett's Oesophagus and Oesophageal Adenocarcinoma

P. Jiménez; E. Piazuelo; C. Cebrian; J. Ortego,; M. Strunk; M. A. GarcíA-Gonzalez; S. Santander; J. Alcedo; A. Lanas

Disclosures

Aliment Pharmacol Ther. ;31(3):440-451. 

In This Article

Abstract and Introduction

Abstract

Background Accumulating evidence suggests that cyclooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) is involved in oesophageal adenocarcinogenesis. PGE2 exerts its biological action by binding to specific receptors (EP1, EP2, EP3 and EP4).
Aim To investigate which PGE2 receptor subtypes regulate PGE2 signals in the oesophageal adenocarcinoma sequence.
Methods Expression was determined in oesophageal biopsies from 85 patients with oesophagitis, Barrett's metaplasia, intraepithelial neoplasia, oesophageal adenocarcinoma and normal oesophagus. Levels of mRNA and protein expression were determined by quantitative PCR, immunohistochemistry and western-blot. Expression of EP receptors was also determined in response to acid and bile exposure in the Barrett's adenocarcinoma cell line OE33.
Results All four EP receptors subtypes were expressed in human oesophageal tissues. COX-2 and, especially, EP2 were increased in the Barrett's metaplasia-intraepithelial neoplasia-adenocarcinoma sequence. Expression of the EP4 receptor protein was increased in oesophageal adenocarcinoma. In contrast, expression levels of COX-1 and EP3 receptor were decreased along the sequence. No differences in EP1 expression were found. Treatment with the bile acid deoxycholate increased COX-2, EP1, EP2 and EP4 expression in OE33 cells.
Conclusions Our data suggest that in addition to COX-2, EP2 and EP4 receptors could be a selective target in the prevention and/or treatment of the Barrett's-associated adenocarcinoma.

Introduction

Barrett's oesophagus, a complication of chronic gastro-oesophageal reflux disease (GERD), is suggested as the most important predisposing factor for the development of adenocarcinoma of the oesophagus. It is estimated to occur in 10% of individuals with chronic GERD and it is associated with an increased risk of developing adenocarcinoma over the general population, estimated at 30-125-fold.[1] Among others, duodenogastro-oesophageal reflux has been established as a strong risk factor in the neoplastic progression of Barrett's oesophagus.[2]

The biological and molecular changes that lead a normal oesophagus to develop oesophageal adenocarcinoma are being unravelled and are an area of growing interest as potential therapeutic targets. In this way, upregulation of COX-2 has been reported in different stages of the carcinogenic sequence of oesophageal cancer and selective COX-2 inhibitors have emerged as an option in the prevention and treatment of oesophageal cancer.[3–7]

Epidemiological studies have shown that the regular use of NSAIDs, which act mainly through the inhibition of COX-1 and COX-2, is associated with a reduced risk of oesophageal cancer.[8–11] A few experimental studies in both animals and humans have suggested that selective COX-2 inhibition delays or reduces the incidence of adenocarcinoma.[12,13] However, recent data have shown that the use of these compounds is associated with an increased risk of adverse cardiovascular events,[14] which suggests the need for new and more selective targets in the PG synthesis pathway downstream of COX.

Prostaglandin E2 mediates the effects of elevated COX-2 in oesophageal adenocarcinoma and exerts its biological action through binding to specific receptors, known as EP receptors. Four subtypes of EP receptors have been identified: EP1, EP2, EP3 and EP4. These receptors differ in structure, binding profiles and use different intracellular signal pathways. Recent studies using genetic deletion and/or pharmacological manipulation of EP receptors with selective agonist/antagonists have shown that EP1, EP2 and EP4 are all implicated in intestinal tumorigenesis.[15–22] Thus, in the present study, we have investigated the expression and precise cellular localization in the human oesophageal adenocarcinoma sequence of the four EP receptors, as well as COX isoenzymes. Furthermore, we determined if exposure of oesophageal cancer cells to acid and bile affected EP receptors expression.

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