title: Prostaglandin E2stimulates urokinase-type plasminogen activator receptor via EP2 receptor-dependent signaling pathways in human AGS gastric cancer cells.
abstract: Aberrant expression of urokinase-type plasminogen activator receptor (uPAR) has been observed in human gastric cancers. Prostaglandin E2(PGE2), whose biosynthesis is catalyzed by cyclooxygenase-2 (COX-2), is implicated in cancer metastasis; however, the cellular and molecular mechanisms of PGE2-driven uPAR expression are yet to be elucidated in human gastric cancer AGS cells. In this study, we showed that PGE2induces uPAR expression in concentration- and time-dependent manners. Furthermore, using antagonists and siRNA, we found that among the four subtypes of PGE2receptors, EP2 receptors are involved in PGE2-induced uPAR expression. PGE2induced the activation of Src, epidermal growth factor receptor (EGFR), c-Jun NH2-terminal kinase (JNK), extracellular signal-regulated kinase (Erk), and p38 mitogen activated protein kinase (p38 MAPK). Specific inhibitor and mutagenesis studies showed that Src, EGFR, JNK1/2, and Erk1/2 are involved in PGE2-induced uPAR expression. PGE2induces EP2-dependent phosphorylation of Src, while the activation of Src-dependent EGFR leads to the phosphorylation of JNK1/2 and Erk1/2. Deletion and site-directed mutagenesis studies demonstrated the involvement of transcription factor activator protein (AP)-1 and nuclear factor-kappa B (NF-κB) in PGE2-induced uPAR expression. EGFR-dependent MAPKs (JNK1/2 and Erk1/2) function as the upstream signaling molecules in the activation of AP-1 and NF-κB, respectively. AGS cells pre-treated with PGE2showed remarkably enhanced invasiveness, which was partially abrogated by uPAR-neutralizing antibodies. To the best of our knowledge, this is the first report that PGE2-induced uPAR expression, which stimulates invasiveness of human gastric cancer AGS cells, is mediated by the EP2 receptor-dependent Src/EGFR/JNK1/2, Erk1/2/AP-1, and Src/EGFR/JNK1/2, Erk1/2/NF-κB cascades. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Sen
authors.initials: S
authors.lastname: Lian
authors.affiliation: Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Trong Thuan
authors.initials: TT
authors.lastname: Ung
authors.affiliation: Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Pham Ngoc
authors.initials: PN
authors.lastname: Khoi
authors.affiliation: Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Hyun Joong
authors.initials: HJ
authors.lastname: Yoon
authors.affiliation: Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Sam Gyu
authors.initials: SG
authors.lastname: Lee
authors.affiliation: Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Kyung Keun
authors.initials: KK
authors.lastname: Kim
authors.affiliation: Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Young Do
authors.initials: YD
authors.lastname: Jung
mesh_terms: D045744:Cell Line, Tumor; D015232:Dinoprostone / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D016328:NF-kappa B / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism*; D015398:Signal Transduction; D013270:Stomach / Q000473:pathology; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D058307:Receptors, Prostaglandin E, EP2 Subtype; D055293:Receptors, Urokinase Plasminogen Activator; D018808:Transcription Factor AP-1; C512478:EGFR protein, human; D066246:ErbB Receptors; D015232:Dinoprostone
keywords: EP2; PGE2; gastric cancer; uPAR