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EGF stimulates uPAR expression and cell invasiveness through ERK, AP-1, and NF-kappaB signaling in human gastric carcinoma cells.
Oncol Rep. 2008 Dec; 20(6):1569-75.OR

Abstract

Overexpression of epidermal growth factor (EGF) and urokinase plasminogen activator receptor (uPAR) have been observed in human gastric cancers. However, the interaction between EGF and uPAR in gastric cancer has not been well elucidated. In this study, we investigated the effect of EGF on uPAR expression and the underlying signal pathways in human gastric cancer AGS cells. EGF induced uPAR mRNA expression in a time- and concentration-dependent manner. EGF also induced uPAR promoter activity. In addition, EGF induced the activation of extracellular signal regulated kinase-1/2 (ERK-1/2) and P38 mitogen-activated protein kinase (MAPK) but not the activation of c-Jun amino terminal kinase. A specific inhibitor of MEK-1 (an upstream effector of ERK-1/2) and a dominant negative MEK-1 were able to suppress the EGF-induced uPAR promoter activity. Site-directed mutagenesis and electrophoretic mobility shift assays demonstrated that the binding sites of transcription factors, activator protein-1 (AP-1) and nuclear factor (NF)-kappaB, are involved in the EGF-induced uPAR transcription. Suppression of the EGF-induced uPAR promoter activity by the AP-1 decoy oligonuclotide, as well as expression vectors encoding mutated-type NF-kappaB-inducting kinase and I-kappaB, confirmed that the activation of AP-1 and NF-kappaB are essential for the EGF-induced uPAR upregulation. The AGS cells pretreated with EGF showed a remarkably enhanced invasiveness and this effect was partially abrogated by uPAR neutralizing antibodies and by the inhibitors of ERK-1/2, AP-1, and NF-kappaB. The above results suggest that EGF induces uPAR expression via ERK-1/2, AP-1, and NF-kappaB signaling pathways and, in turn, stimulates cell invasiveness in human gastric cancer AGS cells.

Authors+Show Affiliations

The Brain Korea 21 Project, Center for Biomedical Human Resources, Chonnam National University Medical School, Kwangju 501-190, Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19020743

Citation

Baek, Min K., et al. "EGF Stimulates uPAR Expression and Cell Invasiveness Through ERK, AP-1, and NF-kappaB Signaling in Human Gastric Carcinoma Cells." Oncology Reports, vol. 20, no. 6, 2008, pp. 1569-75.
Baek MK, Kim MH, Jang HJ, et al. EGF stimulates uPAR expression and cell invasiveness through ERK, AP-1, and NF-kappaB signaling in human gastric carcinoma cells. Oncol Rep. 2008;20(6):1569-75.
Baek, M. K., Kim, M. H., Jang, H. J., Park, J. S., Chung, I. J., Shin, B. A., Ahn, B. W., & Jung, Y. D. (2008). EGF stimulates uPAR expression and cell invasiveness through ERK, AP-1, and NF-kappaB signaling in human gastric carcinoma cells. Oncology Reports, 20(6), 1569-75.
Baek MK, et al. EGF Stimulates uPAR Expression and Cell Invasiveness Through ERK, AP-1, and NF-kappaB Signaling in Human Gastric Carcinoma Cells. Oncol Rep. 2008;20(6):1569-75. PubMed PMID: 19020743.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - EGF stimulates uPAR expression and cell invasiveness through ERK, AP-1, and NF-kappaB signaling in human gastric carcinoma cells. AU - Baek,Min K, AU - Kim,Mi H, AU - Jang,Hee J, AU - Park,Jung S, AU - Chung,Ik J, AU - Shin,Boo A, AU - Ahn,Bong W, AU - Jung,Young D, PY - 2008/11/21/pubmed PY - 2009/2/5/medline PY - 2008/11/21/entrez SP - 1569 EP - 75 JF - Oncology reports JO - Oncol Rep VL - 20 IS - 6 N2 - Overexpression of epidermal growth factor (EGF) and urokinase plasminogen activator receptor (uPAR) have been observed in human gastric cancers. However, the interaction between EGF and uPAR in gastric cancer has not been well elucidated. In this study, we investigated the effect of EGF on uPAR expression and the underlying signal pathways in human gastric cancer AGS cells. EGF induced uPAR mRNA expression in a time- and concentration-dependent manner. EGF also induced uPAR promoter activity. In addition, EGF induced the activation of extracellular signal regulated kinase-1/2 (ERK-1/2) and P38 mitogen-activated protein kinase (MAPK) but not the activation of c-Jun amino terminal kinase. A specific inhibitor of MEK-1 (an upstream effector of ERK-1/2) and a dominant negative MEK-1 were able to suppress the EGF-induced uPAR promoter activity. Site-directed mutagenesis and electrophoretic mobility shift assays demonstrated that the binding sites of transcription factors, activator protein-1 (AP-1) and nuclear factor (NF)-kappaB, are involved in the EGF-induced uPAR transcription. Suppression of the EGF-induced uPAR promoter activity by the AP-1 decoy oligonuclotide, as well as expression vectors encoding mutated-type NF-kappaB-inducting kinase and I-kappaB, confirmed that the activation of AP-1 and NF-kappaB are essential for the EGF-induced uPAR upregulation. The AGS cells pretreated with EGF showed a remarkably enhanced invasiveness and this effect was partially abrogated by uPAR neutralizing antibodies and by the inhibitors of ERK-1/2, AP-1, and NF-kappaB. The above results suggest that EGF induces uPAR expression via ERK-1/2, AP-1, and NF-kappaB signaling pathways and, in turn, stimulates cell invasiveness in human gastric cancer AGS cells. SN - 1021-335X UR - https://www.unboundmedicine.com/medline/citation/19020743/EGF_stimulates_uPAR_expression_and_cell_invasiveness_through_ERK_AP_1_and_NF_kappaB_signaling_in_human_gastric_carcinoma_cells_ L2 - http://www.spandidos-publications.com/or/20/6/1569 DB - PRIME DP - Unbound Medicine ER -