Tags

Type your tag names separated by a space and hit enter

Prostaglandin E2 stimulates urokinase-type plasminogen activator receptor via EP2 receptor-dependent signaling pathways in human AGS gastric cancer cells.
Mol Carcinog. 2017 02; 56(2):664-680.MC

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 PGE2 induces uPAR expression in concentration- and time-dependent manners. Furthermore, using antagonists and siRNA, we found that among the four subtypes of PGE2 receptors, EP2 receptors are involved in PGE2 -induced uPAR expression. PGE2 induced 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. PGE2 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 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 PGE2 showed 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+Show Affiliations

Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea.Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea.Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea.Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea.Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea.Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea.Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea.Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27377703

Citation

Lian, Sen, et al. "Prostaglandin E2 Stimulates Urokinase-type Plasminogen Activator Receptor Via EP2 Receptor-dependent Signaling Pathways in Human AGS Gastric Cancer Cells." Molecular Carcinogenesis, vol. 56, no. 2, 2017, pp. 664-680.
Lian S, Xia Y, Ung TT, et al. Prostaglandin E2 stimulates urokinase-type plasminogen activator receptor via EP2 receptor-dependent signaling pathways in human AGS gastric cancer cells. Mol Carcinog. 2017;56(2):664-680.
Lian, S., Xia, Y., Ung, T. T., Khoi, P. N., Yoon, H. J., Lee, S. G., Kim, K. K., & Jung, Y. D. (2017). Prostaglandin E2 stimulates urokinase-type plasminogen activator receptor via EP2 receptor-dependent signaling pathways in human AGS gastric cancer cells. Molecular Carcinogenesis, 56(2), 664-680. https://doi.org/10.1002/mc.22524
Lian S, et al. Prostaglandin E2 Stimulates Urokinase-type Plasminogen Activator Receptor Via EP2 Receptor-dependent Signaling Pathways in Human AGS Gastric Cancer Cells. Mol Carcinog. 2017;56(2):664-680. PubMed PMID: 27377703.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Prostaglandin E2 stimulates urokinase-type plasminogen activator receptor via EP2 receptor-dependent signaling pathways in human AGS gastric cancer cells. AU - Lian,Sen, AU - Xia,Yong, AU - Ung,Trong Thuan, AU - Khoi,Pham Ngoc, AU - Yoon,Hyun Joong, AU - Lee,Sam Gyu, AU - Kim,Kyung Keun, AU - Jung,Young Do, Y1 - 2016/07/27/ PY - 2015/12/07/received PY - 2016/06/27/revised PY - 2016/07/01/accepted PY - 2016/7/6/pubmed PY - 2017/9/2/medline PY - 2016/7/6/entrez KW - EP2 KW - PGE2 KW - gastric cancer KW - uPAR SP - 664 EP - 680 JF - Molecular carcinogenesis JO - Mol Carcinog VL - 56 IS - 2 N2 - 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 PGE2 induces uPAR expression in concentration- and time-dependent manners. Furthermore, using antagonists and siRNA, we found that among the four subtypes of PGE2 receptors, EP2 receptors are involved in PGE2 -induced uPAR expression. PGE2 induced 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. PGE2 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 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 PGE2 showed 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. SN - 1098-2744 UR - https://www.unboundmedicine.com/medline/citation/27377703/Prostaglandin_E2_stimulates_urokinase_type_plasminogen_activator_receptor_via_EP2_receptor_dependent_signaling_pathways_in_human_AGS_gastric_cancer_cells_ L2 - https://doi.org/10.1002/mc.22524 DB - PRIME DP - Unbound Medicine ER -