In:
Molecular Carcinogenesis, Wiley, Vol. 56, No. 2 ( 2017-02), p. 664-680
Abstract:
Aberrant expression of urokinase‐type plasminogen activator receptor (uPAR) has been observed in human gastric cancers. Prostaglandin E 2 (PGE 2 ), whose biosynthesis is catalyzed by cyclooxygenase‐2 (COX‐2), is implicated in cancer metastasis; however, the cellular and molecular mechanisms of PGE 2 ‐driven uPAR expression are yet to be elucidated in human gastric cancer AGS cells. In this study, we showed that PGE 2 induces uPAR expression in concentration‐ and time‐dependent manners. Furthermore, using antagonists and siRNA, we found that among the four subtypes of PGE 2 receptors, EP2 receptors are involved in PGE 2 ‐induced uPAR expression. PGE 2 induced the activation of Src, epidermal growth factor receptor (EGFR), c‐Jun NH 2 ‐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 PGE 2 ‐induced uPAR expression. PGE 2 induces 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 PGE 2 ‐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 PGE 2 showed remarkably enhanced invasiveness, which was partially abrogated by uPAR‐neutralizing antibodies. To the best of our knowledge, this is the first report that PGE 2 ‐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.
Type of Medium:
Online Resource
ISSN:
0899-1987
,
1098-2744
Language:
English
Publisher:
Wiley
Publication Date:
2017
detail.hit.zdb_id:
2001984-1
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