Authors: Jurairat Jongthawin Porncheera Chusorn Anchalee Techasen Watcharin Loilome Thidarut Boonmars Raynoo Thanan Anucha Puapairoj Narong Khuntikeo Wichittra Tassaneeyakul Puangrat Yongvanit Nisana Namwat
Publish Date: 2014/05/18
Volume: 35, Issue: 8, Pages: 8051-8064
Abstract
Prostaglandin E2 PGE2 involves in progression of various chronic inflammationrelated cancers including cholangiocarcinoma CCA This study aimed to determine the role of PGE2 signaling its biosynthesisrelated enzymes in a clinical prognosis and their targeted inhibition in CCA progression The immunohistochemical staining of cyclooxygenase COX1 COX2 mPGES1 EP1 and EP4 was examined in CCA tissues and their expressions were compared with clinicopathological parameters The effect of PGE2 on levels of its signaling molecules was examined in CCA cell lines using proteome profiler array The suppression of mPGES1 using a smallmolecule inhibitor CAY10526 and small interfering RNA siRNA was determined for growth and migration ability in CCA cells The results indicated that strong expressions of COX1 COX2 mPGES1 EP1 and EP4 were found in CCA tissues as 875 475 525 55 and 80 of frequencies respectively High mPGES1 expression was significantly correlated with tumor stages III–IV p = 0001 lymph node metastasis p = 0004 shorter survival p = 0009 and prognostic indicator of CCA patients HR = 2512 p = 0041 Expressions of COX1 COX2 and EP receptors did not correlate with data tested from patients PGE2 markedly enhanced protein levels of integrinα6 VEcadherin Jagged1 and Notch3 and CAY10526 suppressed those protein levels as well as PGE2 production in CCA cells CAY10526 and siRNA mPGES1 markedly suppressed mPGES1 protein levels growth and migration abilities of CCA cell lines In conclusion PGE2 signaling strongly promotes CCA progression Therefore inhibition of PGE2 synthesis by suppression of its biosynthesisrelated enzymes could be useful for prevention and treatment of CCAThis work was supported by the Higher Education Research Promotion and National Research University Project of Thailand Office of the Higher Education Commission through the Health Cluster SHePGMS Khon Kaen University to NN a grant from a MidCareer Grant RSA5280007 Thailand Research Fund to NN a grant fund for the PhD program to JJ and the Research Assistantship grant AS56202 from the Faculty of Medicine Khon Kaen University Thailand to NN We thank Associate Professor Ross Andrews University of South Australia Adelaide South Australia Australia for assistance with the presentation of this paper
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