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. 2012;31(3):440-451. 

In This Article

Discussion

The present study describes for the first time the profile of expression of EP receptors in human oesophageal tissues of patients with different pathological conditions linked to gastro-oesophageal reflux diseases. Our study has shown that COX-2 and, overall, EP2 receptor expression have a marked increase in all stages of the oesophageal adenocarcinogenetic sequence, in contrast with a decrease observed for the EP3 receptor. EP4 receptors were also increased in oesophageal adenocarcinoma.

Different studies have already reported upregulation of COX-2 at different stages of the oesophageal carcinogenic sequence;[3–7] however, there are some discrepancies regarding when the overexpression occurs. Our study demonstrates that COX-2 is detected in macroscopically normal oesophagus and that it is upregulated progressively along the carcinogenetic sequence, reaching the highest level in high-grade intraepithelial neoplasia and adenocarcinoma. Using this information, COX-2 has been seen as a molecular target in the prevention and treatment of oesophageal cancer,[12,13] but, as commented above, the use of COX-2 selective inhibitors has been associated with serious cardiovascular events,[14,27] which will prevent their use as chemopreventive agents. Based on these facts, there is a clear need for the identification of more selective targets in the PG synthesis pathway downstream of COX, including prostaglandin E2 receptors.[15–22]

In a rat experimental model of oesophageal tumorigenesis, chronic duodenal reflux increased mRNA levels of EP2, EP3 and EP4, but not EP1 receptors in the oesophageal mucosa.[28] Recently, we found that the selective EP2 agonist Butaprost significantly inhibited butyrate-induced apoptosis and stimulated migration of OE33 cells, but cell proliferation and migration were inhibited or attenuated with EP1 and EP4 antagonists.[25]

The results of the current study suggest that all EP receptors are expressed in oesophageal tissues and that overexpression of the EP2 receptor occurs in all stages of carcinogenetic sequence; however, the greater increase in expression occurs in the early phases of the sequence (Barrett's metaplasia without intraepithelial neoplasia and in low-grade intraepithelial neoplasia). This interesting finding was consistent, as it was observed both at mRNA level and at protein level. Expression of EP4 receptor is also increased in damaged oesophageal tissues, but the increase is less significant than that observed with the EP2 receptor. Although there was no positive correlation between EP4 mRNA and protein expression, immunohistochemical evaluation demonstrates that levels of EP4 protein expression increased in oesophageal adenocarcinoma with respect to normal oesophagus. This aspect will be necessary to confirm in the future and to study the possible post-transcriptional mechanisms implied.

Downregulation of EP3 receptor has been found in colon cancer of mice, rats and humans and DNA methylation could be the mechanism involved in reduced gene expression.[29] In our study, we found a marked loss of EP3 protein expression along Barrett's metaplasia-intraepithelial neoplasia-adenocarcinoma sequence, suggesting that low levels of EP3 receptor could be also related to oesophageal cancer development.

Moreover, our data suggest that deoxycholic acid induces EP1, EP2 and EP4 receptor expression in OE33 cells and, although the level of induction was significantly lower compared with COX-2 induction, the study demonstrates that endogenous inducers of COX-2 and PGE2 also induce expression of EP receptors.[5,25,30]

Other studies have also found an involvement of EP2 receptors in tumour progression.[31,32] PGE2 is involved in tumour development, primarily by stimulating proliferation and angiogenesis and also by inhibition of apoptosis. All these processes are mediated, at least in part, by binding to EP2 receptors. Thus, EP2 receptor activation increases VEGF expression in colon, pancreatic and mammary cancer.[19,33,34] In skin carcinogenesis, proliferation and hyperplasia are also partially mediated by the activation of the EP2 receptor.[35]

In the future, it will be important to define which EP receptors mediate the physiological processes exerted by PGE2. At the gastrointestinal level, it has been reported that the EP3 receptor is involved in duodenal bicarbonate secretion and maintenance of mucosal integrity[36] and that EP3 and EP4 are essential for maintaining the mucosal integrity of the duodenum.[37] In the stomach, the gastric cytoprotective action of PGE2 is mediated by the activation of EP1 receptors and EP4 receptor mediates mucus secretion in rabbit gastric epithelial cells.[38,39]

Finally, although it is widely accepted that COX-1 is a constitutively expressed isoform which generates prostaglandins under basal conditions for normal physiological functions, recent investigations have suggested a possible role for COX-1 in oesophageal carcinogenesis. Thus, it has shown COX-1 and COX-2 expression is strongly linked to expression of angiogenic factors.[40] Other authors showed that COX-1 expression decreased in oesophageal neoplasic tissues compared with normal oesophagus.[41,42] In accordance with these previous studies, our results show that COX-1 is downregulated in both Barrett's oesophagus and adenocarcinoma tissues. In view of these data, additional studies are needed to clarify the exact role of COX-1 in the oesophageal carcinogenesis process.

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