Prostaglandin receptor EP3 regulates cell proliferation and migration with impact on survival of endometrial cancer patients
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Junyan Zhu1,2, Fabian Trillsch1, Doris Mayr3, Christina Kuhn1, Martina Rahmeh1, Simone Hofmann1, Marianne Vogel1, Sven Mahner1, Udo Jeschke1 and Viktoria von Schönfeldt4
1Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Munich, Germany
2Department of Gynecology and Obstetrics, Shanghai Jiao Tong University, School of Medicine, Renji Hospital, Shanghai, China
3Department of Pathology, University Hospital, LMU Munich, Munich, Germany
4Division of Gynecological Endocrinology and Reproductive Medicine, Department of Gynecology and Obstetrics, University Hospital, LMU Munich, Munich, Germany
Fabian Trillsch, email: [email protected]
Keywords: prostaglandin receptor EP3; endometrial cancer; prognosis; estrogen receptor β; Ras
Received: May 23, 2017 Accepted: November 16, 2017 Published: December 09, 2017
Background: Prostaglandin E2 (PGE2) receptor 3 (EP3) regulates tumor cell proliferation, migration, and invasion in numerous cancers. The role of EP3 as a prognostic biomarker in endometrial cancer remains unclear. The primary aim of this study was to analyze the prognostic significance of EP3 expression in endometrial cancer.
Methods: We analyzed the EP3 expression of 140 endometrial carcinoma patients by immunohistochemistry. RL95-2 endometrial cancer cell line was chosen from four endometrial cancer cell lines (RL95-2, Ishikawa, HEC-1-A, and HEC-1-B) according to EP3 expression level. Treated with PGE2 and EP3 antagonist, RL95-2 cells were investigated by MTT, BrdU, and wound healing assay for functional assessment of EP3.
Results: EP3 staining differed significantly according to WHO tumor grading in both whole cohort (p = 0.01) and the subgroup of endometrioid carcinoma (p = 0.01). Patients with high EP3 expression in their respective tumors had impaired progression-free survival as well as overall survival in both cohorts above. EP3 expression in the overall cohort was identified as an independent prognostic marker for progression-free survival (HR 1.014, 95%CI 1.003-1.024, p = 0.01) when adjusted for age, stage, grading, and recurrence. Treatment with EP3 antagonists induced upregulation of estrogen receptor β and decreased activity of Ras and led to attenuated proliferation and migration of RL95-2 cells.
Conclusions: EP3 seems to play a crucial role in endometrial cancer progression. In the context of limited systemic treatment options for endometrial cancer, this explorative analysis identifies EP3 as a potential target for diagnostic workup and therapy.
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