EGF stimulates uPAR expression and cell invasiveness through ERK, AP-1, and NF-κB signaling in human gastric carcinoma cells

  • Authors:
    • Min K. Baek
    • Mi H. Kim
    • Hee J. Jang
    • Jung S. Park
    • Ik J. Chung
    • Boo A. Shin
    • Bong W. Ahn
    • Young D. Jung
  • View Affiliations

  • Published online on: December 1, 2008     https://doi.org/10.3892/or_00000181
  • Pages: 1569-1575
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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)-κB, 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-κB-inducting kinase and I-κB, confirmed that the activation of AP-1 and NF-κB 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-κB. The above results suggest that EGF induces uPAR expression via ERK-1/2, AP-1, and NF-κB signaling pathways and, in turn, stimulates cell invasiveness in human gastric cancer AGS cells.

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December 2008
Volume 20 Issue 6

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Baek MK, Kim MH, Jang HJ, Park JS, Chung IJ, Shin BA, Ahn BW and Jung YD: EGF stimulates uPAR expression and cell invasiveness through ERK, AP-1, and NF-κB signaling in human gastric carcinoma cells. Oncol Rep 20: 1569-1575, 2008
APA
Baek, M.K., Kim, M.H., Jang, H.J., Park, J.S., Chung, I.J., Shin, B.A. ... Jung, Y.D. (2008). EGF stimulates uPAR expression and cell invasiveness through ERK, AP-1, and NF-κB signaling in human gastric carcinoma cells. Oncology Reports, 20, 1569-1575. https://doi.org/10.3892/or_00000181
MLA
Baek, M. K., Kim, M. H., Jang, H. J., Park, J. S., Chung, I. J., Shin, B. A., Ahn, B. W., Jung, Y. D."EGF stimulates uPAR expression and cell invasiveness through ERK, AP-1, and NF-κB signaling in human gastric carcinoma cells". Oncology Reports 20.6 (2008): 1569-1575.
Chicago
Baek, M. K., Kim, M. H., Jang, H. J., Park, J. S., Chung, I. J., Shin, B. A., Ahn, B. W., Jung, Y. D."EGF stimulates uPAR expression and cell invasiveness through ERK, AP-1, and NF-κB signaling in human gastric carcinoma cells". Oncology Reports 20, no. 6 (2008): 1569-1575. https://doi.org/10.3892/or_00000181