Prostaglandin E<sub>2sub> stimulates urokinase-type plasminogen activator receptor via EP2 receptor-dependent signaling pathways in human AGS gastric cancer cells

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• 作者：Sen Lian ; Yong Xia ; Trong Thuan Ung ; Pham Ngoc Khoi ; Hyun Joong Yoon ; Sam Gyu Lee ; Kyung Keun Kim and Young Do Jung
• 刊名：Molecular Carcinogenesis
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：56
• 期：2
• 页码：664-680
• 全文大小：5338K
• ISSN：1098-2744

文摘

Aberrant expression of urokinase-type plasminogen activator receptor (uPAR) has been observed in human gastric cancers. Prostaglandin E<sub>2sub> (PGE<sub>2sub>), whose biosynthesis is catalyzed by cyclooxygenase-2 (COX-2), is implicated in cancer metastasis; however, the cellular and molecular mechanisms of PGE<sub>2sub>-driven uPAR expression are yet to be elucidated in human gastric cancer AGS cells. In this study, we showed that PGE<sub>2sub> induces uPAR expression in concentration- and time-dependent manners. Furthermore, using antagonists and siRNA, we found that among the four subtypes of PGE<sub>2sub> receptors, EP2 receptors are involved in PGE<sub>2sub>-induced uPAR expression. PGE<sub>2sub> induced the activation of Src, epidermal growth factor receptor (EGFR), c-Jun NH<sub>2sub>-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<sub>2sub>-induced uPAR expression. PGE<sub>2sub> 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<sub>2sub>-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<sub>2sub> 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<sub>2sub>-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.