Yao Ye1,2, Lin Peng2, Aurelia Vattai2, Eileen Deuster2, Christina Kuhn2, Christian Dannecker3, Sven Mahner2, Udo Jeschke4,5, Viktoria von Schönfeldt2, Helene H Heidegger2. 1. Department of Gynecology and Obstetrics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 2. Department of Obstetrics and Gynecology, University Hospital, Ludwig-Maximilians University of Munich, Campus Großhadern: Marchioninistraße 15, 81377, Munich, Germany. 3. Department of Obstetrics and Gynecology, University Hospital, University of Augsburg, Augsburg, Germany. 4. Department of Obstetrics and Gynecology, University Hospital, Ludwig-Maximilians University of Munich, Campus Großhadern: Marchioninistraße 15, 81377, Munich, Germany. Udo.Jeschke@med.uni-muenchen.de. 5. Department of Obstetrics and Gynecology, University Hospital, University of Augsburg, Augsburg, Germany. Udo.Jeschke@med.uni-muenchen.de.
Abstract
PURPOSE: Cervical cancer metastasis results in poor prognosis and increased mortality, which is not separated from inflammatory reactions accumulated by prostaglandin E2 (PGE2). As a specific G-protein coupled PGE2 receptor, EP3 is demonstrated as a negative prognosticator of cervical malignancy. Now, we aimed to investigate the pathological mechanism of EP3 in modulating cervical cancer carcinogenesis. METHODS: Bioinformatics analysis was used to identify PAI-1 and uPAR correlations with EP3 expression, as well as the prognosis of cervical cancer patients. In vitro analyses were carried out to investigate the role of EP3 on cervical cancer proliferation and migration. RESULTS: In vitro studies showed that sulprostone (an EP3 agonist) enhanced the proliferation and migration of cervical cancer cells, whereas silencing of EP3 inhibited their proliferation and migration. Furthermore, EP3 knockdown increased the expression of plasminogen activator inhibitor type 1 (PAI-1), urokinase-type plasminogen activator receptor (uPAR), and phosphorylated extracellular signal-regulated kinases 1/2 (p-ERK1/2), but decreased p53 expression. Bioinformatics analysis showed that both PAI-1 and uPAR were correlated with EP3 expression, as well as the prognosis of cervical cancer patients. The survival analysis further showed that uPAR overexpression (IRS≥2) was correlated with a lower overall survival rate of cervical cancer patients with advanced stages (FIGO III-IV). CONCLUSION: These results indicated that EP3 signaling pathway might facilitate the migration of cervical cancer cells through modulating uPAR expression. Therefore, EP3 and uPAR could represent novel therapeutic targets in the treatment of cervical cancer in advantaged stages.
PURPOSE:Cervical cancer metastasis results in poor prognosis and increased mortality, which is not separated from inflammatory reactions accumulated by prostaglandin E2 (PGE2). As a specific G-protein coupled PGE2 receptor, EP3 is demonstrated as a negative prognosticator of cervical malignancy. Now, we aimed to investigate the pathological mechanism of EP3 in modulating cervical cancer carcinogenesis. METHODS: Bioinformatics analysis was used to identify PAI-1 and uPAR correlations with EP3 expression, as well as the prognosis of cervical cancerpatients. In vitro analyses were carried out to investigate the role of EP3 on cervical cancer proliferation and migration. RESULTS: In vitro studies showed that sulprostone (an EP3 agonist) enhanced the proliferation and migration of cervical cancer cells, whereas silencing of EP3 inhibited their proliferation and migration. Furthermore, EP3 knockdown increased the expression of plasminogen activator inhibitor type 1 (PAI-1), urokinase-type plasminogen activator receptor (uPAR), and phosphorylated extracellular signal-regulated kinases 1/2 (p-ERK1/2), but decreased p53 expression. Bioinformatics analysis showed that both PAI-1 and uPAR were correlated with EP3 expression, as well as the prognosis of cervical cancerpatients. The survival analysis further showed that uPAR overexpression (IRS≥2) was correlated with a lower overall survival rate of cervical cancerpatients with advanced stages (FIGO III-IV). CONCLUSION: These results indicated that EP3 signaling pathway might facilitate the migration of cervical cancer cells through modulating uPAR expression. Therefore, EP3 and uPAR could represent novel therapeutic targets in the treatment of cervical cancer in advantaged stages.