Prostaglandin E2 (PGE2) promotes proliferation and invasion by enhancing SUMO-1 activity via EP4 receptor in endometrial cancer.

Jieqi Ke,Huilin Zhang,Xiaofang Yan,Fangyuan Wang,Xiaojun Wang,Zheng Chen,Qi Che,Minjiao Zhu,Feizhou Jiang,Chenyun Dai,Xiaoping Wan,Huihui Wang,Huan Tong,Yixia Yang,Yuan Liu

doi:10.1007/s13277-016-5087-x

Abstract

Prostaglandin E2 (PGE2), a derivative of arachidonic acid, has been identified as a tumorigenic factor in many cancers in recent studies. Prostaglandin E synthase 2 (PTGES2) is an enzyme that in humans is encoded by the PTGES2 gene located on chromosome 9, and it synthesizes PGE2 in human cells. In our study, we selected 119 samples from endometrial cancer patients, with 50 normal endometrium tissue samples as controls, in which we examined the expression of PTGES2. Both immunohistochemistry (IHC) and Western blot analyses demonstrated that synthase PTGES2, which is required for PGE2 synthesis, was highly expressed in endometrium cancer tissues compared with normal endometrium. Stable PTGES2-shRNA transfectants were generated in Ishikawa and Hec-1B endometrial cancer cell lines, and transfection efficiencies were confirmed by RT-PCR and Western blot analyses. We found that PGE2 promoted proliferation and invasion of cells in Ishikawa and Hec-1B cells by cell counting kit-8 tests (CCK8) and transwell assays, respectively. PGE2 stimulation enhanced the expression of SUMO-1, via PGE2 receptor subtype 4 (EP4). Further analysis implicated the Wnt/β-catenin signaling pathway function as the major mediator of EP4 and SUMO-1. The increase in SUMO-1 activity prompted the SUMOlyation of target proteins which may be involved in proliferation and invasion. These findings suggest SUMO-1 and EP4 as two potential targets for new therapeutic or prevention strategies for endometrial cancers.

Highlights

Endometrial cancer is the most common tumor of the female reproductive system in developed countries [1]
This study investigated the role of Prostaglandin E2 (PGE2), via its receptor EP4, in the promotion of Small ubiquitin-like modifier (SUMO)-1 expression, and identified that this regulation occurs through Wnt/β-catenin signaling pathway, resulting in the enhancement of proliferation and invasion of endometrial cancer cells
Compared with the normal endometrium, the expression of Prostaglandin E synthase 2 (PTGES2) was significantly upregulated in the endometrial cancer tissues (Fig. 1a, b; Table 2).By statistical analysis, we found that increased expression of PTGES2 was notably associated with the tumor stage (P = 0.0088), grade (P = 0.0104), and the depth of myometrial invasion (P = 0.0015), but not with other characteristics (Table 3)

Summary

Introduction

Endometrial cancer is the most common tumor of the female reproductive system in developed countries [1]. In the US, endometrial cancer results in about 8,590 death cases per year [2], while in developing countries, such as China, the mortality incidence is approximately 7.44/105 people [3]. Many studies have found PGE2 associated with tumors of the colorectal organs, lung, and breast [5,6,7]. In some before studies of our research teams, we have found some cytokines high expressed in endometrial cancers [8, 9], and PGE2 is one of them. Some previous studies have suggested that PGE2 participates in tumorigenesis of endometrial cancers [10, 11]; the definite effect and its detailed mechanisms are unclear, which promotes us interest in PGE2

Methods

Results

Conclusion