Prostaglandin E2 receptor 3 (EP3) signaling promotes migration of cervical cancer via urokinase-type plasminogen activator receptor (uPAR)

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. Electronic supplementary material The online version of this article (10.1007/s00432-020-03272-0) contains supplementary material, which is available to authorized users.

Piperine Reduces Neoplastic Progression in Cervical Cancer Cells by Downregulating the Cyclooxygenase 2 Pathway

“…In addition, inflammation is triggered in the presence of the virus; when the infection persists, the inflammation that previously contained the virus becomes chronic and is responsible for progression to a neoplasm [ 2 , 6 ]. Chronic inflammation is present in about 20% of human cancers and is the main inducer of malignancy by promoting metastasis and angiogenesis [ 7 , 8 ].…”

The Interaction of Human Papillomavirus Infection and Prostaglandin E2 Signaling in Carcinogenesis: A Focus on Cervical Cancer Therapeutics

“…PTGER2 expression is a prognostic factor for the overall survival in the subgroup of negative PTGER3, and high galectin-3 expressed cervical cancer patients [ 124 ]. PTGER3 signaling promotes the migration of cervical cancer cells through the modulation of the urokinase-type plasminogen activator receptor [ 125 ]. Hence, the COX-2/PGE 2 /PTGERs axis plays an important role in the inflammatory environment seen in cervical cancer development.…”

Immunological significance of alternative splicing prognostic signatures for bladder cancer

“…Due to the unique structure of PTGER3, it can form at least 8 different splice isoforms, which are widely distributed in a variety of tissues and organs throughout the body and participate in numerous physiological and pathological activities, such as promoting uterine contraction during pregnancy, regulating bladder micturition and stimulating inflammatory swelling [38,39,40]. In addition, PTGER3 mediates tumor lymphangiogenesis and the occurrence of many kinds of tumors, but the regulatory modes conflict with each other [41,42,43,44,45]. To study the role of PTGER3 in BLCA, we further verified it.…”