Prostaglandin receptor EP3 regulates cell proliferation and migration with impact on survival of endometrial cancer patients

// Junyan Zhu 1, 2 , Fabian Trillsch 1 , Doris Mayr 3 , Christina Kuhn 1 , Martina Rahmeh 1 , Simone Hofmann 1 , Marianne Vogel 1 , Sven Mahner 1 , Udo Jeschke 1 and Viktoria von Schonfeldt 4 1 Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Munich, Germany 2 Department of Gynecology and Obstetrics, Shanghai Jiao Tong University, School of Medicine, Renji Hospital, Shanghai, China 3 Department of Pathology, University Hospital, LMU Munich, Munich, Germany 4 Division of Gynecological Endocrinology and Reproductive Medicine, Department of Gynecology and Obstetrics, University Hospital, LMU Munich, Munich, Germany Correspondence to: Fabian Trillsch, email: Fabian.Trillsch@med.uni-muenchen.de Keywords: prostaglandin receptor EP3; endometrial cancer; prognosis; estrogen receptor β; Ras Received: May 23, 2017 Accepted: November 16, 2017 Published: December 09, 2017 ABSTRACT 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.