TY - JOUR
T1 - Characterization of the prostaglandin E 2 pathway in a rat model of esophageal adenocarcinoma
AU - Piazuelo, E.
AU - Santander, S.
AU - Cebrián, C.
AU - Jiménez, P.
AU - Pastor, C.
AU - García-González, M. A.
AU - Esteva, F.
AU - Esquivias, P.
AU - Ortego, J.
AU - Lanas, A.
PY - 2012/2
Y1 - 2012/2
N2 - Accumulating evidence indicates that the cyclooxygenase-2 (COX-2)/prostaglandin E 2(PGE 2) pathway plays a key role in esophageal carcinogenesis. A better understanding of the pathway downstream of COX-2 may reveal novel targets for the prevention of esophageal adenocarcinoma (EAC). The objective of this study was to characterize the profile of genes involved in PGE 2metabolism and signaling in an experimental model of EAC. Esophagojejunostomy with gastric preservation was performed in wistar rats to induce gastroduodenal reflux. Rats were sacrificed 2 or 4 months after surgery. Nine non-operated rats were used to obtain normal (control) esophageal tissues. RESULTS: All rats that underwent esophagojejunostomy developed inflammation. In addition, 90% of the animals showed intestinal metaplasia; of those, 40% progressed to AC. This process was accompanied by a significant increase in esophageal PGE 2levels and the induction of both mRNA and protein levels of COX-2, COX-1, prostaglandin E synthase, 15-hydroxyprostaglandin dehydrogenase, and PGE 2receptors EP3, EP4 and especially EP2, which rose to particularly high levels in experimental rats. In addition, exposure to a selective COX-2 inhibitor (SC58125) or an EP1/EP2 antagonist (AH6809), but not an EP4 antagonist (AH23848B), significantly reduced cell proliferation of esophageal explants in 24 hour-organ culture experiments. Our data suggest that, in addition to COX-2, other components of the PGE 2pathway, including COX-1, may play important roles in the development of EAC induced by gastroduodenal reflux in the rat. Although it must be confirmed in vivo, the EP2 receptor may represent a promising selective target in the prevention of Barrett's associated AC.
AB - Accumulating evidence indicates that the cyclooxygenase-2 (COX-2)/prostaglandin E 2(PGE 2) pathway plays a key role in esophageal carcinogenesis. A better understanding of the pathway downstream of COX-2 may reveal novel targets for the prevention of esophageal adenocarcinoma (EAC). The objective of this study was to characterize the profile of genes involved in PGE 2metabolism and signaling in an experimental model of EAC. Esophagojejunostomy with gastric preservation was performed in wistar rats to induce gastroduodenal reflux. Rats were sacrificed 2 or 4 months after surgery. Nine non-operated rats were used to obtain normal (control) esophageal tissues. RESULTS: All rats that underwent esophagojejunostomy developed inflammation. In addition, 90% of the animals showed intestinal metaplasia; of those, 40% progressed to AC. This process was accompanied by a significant increase in esophageal PGE 2levels and the induction of both mRNA and protein levels of COX-2, COX-1, prostaglandin E synthase, 15-hydroxyprostaglandin dehydrogenase, and PGE 2receptors EP3, EP4 and especially EP2, which rose to particularly high levels in experimental rats. In addition, exposure to a selective COX-2 inhibitor (SC58125) or an EP1/EP2 antagonist (AH6809), but not an EP4 antagonist (AH23848B), significantly reduced cell proliferation of esophageal explants in 24 hour-organ culture experiments. Our data suggest that, in addition to COX-2, other components of the PGE 2pathway, including COX-1, may play important roles in the development of EAC induced by gastroduodenal reflux in the rat. Although it must be confirmed in vivo, the EP2 receptor may represent a promising selective target in the prevention of Barrett's associated AC.
KW - 15-hydroxyprostaglandin dehydrogenase
KW - Barrett's esophagus
KW - Cyclooxygenase
KW - EP receptors
KW - Esophageal adenocarcinoma
KW - Prostaglandin E
KW - Prostaglandin E synthase
UR - http://www.scopus.com/inward/record.url?scp=84856431512&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84856431512&partnerID=8YFLogxK
U2 - 10.2174/156800912799095199
DO - 10.2174/156800912799095199
M3 - Article
C2 - 22165968
AN - SCOPUS:84856431512
SN - 1568-0096
VL - 12
SP - 132
EP - 143
JO - Current cancer drug targets
JF - Current cancer drug targets
IS - 2
ER -