Cadmium induces urokinase-type plasminogen activator receptor expression and the cell invasiveness of human gastric cancer cells via the ERK-1/2, NF-κB, and AP-1 signaling pathways

  • Authors:
    • Pham Ngoc Khoi
    • Yong Xia
    • Sen Lian
    • Ho Dong Kim
    • Do Hyun Kim
    • Young Eun Joo
    • Kee-Oh Chay
    • Kyung Keun Kim
    • Young Do Jung
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  • Published online on: July 22, 2014     https://doi.org/10.3892/ijo.2014.2558
  • Pages: 1760-1768
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Abstract

Cadmium exposure has been linked to human cancers, including stomach cancer. In this study, the effects of cadmium on urokinase-type plasminogen activator receptor (uPAR) expression in human gastric cancer cells and the underlying signal transduction pathways were investigated. Cadmium induced uPAR expression in a time- and concentration-dependent manner. Cadmium also induced uPAR promoter activity. Additionally, cadmium induced the activation of extracellular signal regulated kinase-1/2 (ERK-1/2), p38 mitogen-activated protein kinase (MAPK), and the activation of c-Jun amino terminal kinase (JNK). A specific inhibitor of MEK-1 (PD98059) inhibited cadmium-induced uPAR expression, while JNK and p38 MAPK inhibitors did not. Expression vectors encoding dominant-negative MEK-1 (pMCL-K97M) also prevented cadmium-induced uPAR promoter activity. Site-directed mutagenesis and electrophoretic mobility shift studies showed that sites for the transcription factors nuclear factor (NF)-κB and activator protein-1 (AP-1) were involved in cadmium-induced uPAR transcription. Suppression of the cadmium-induced uPAR promoter activity by a mutated-type NF-κB-inducing kinase and I-κB and an AP-1 decoy oligonucleotide confirmed that the activation of NF-κB and AP-1 are essential for cadmium-induced uPAR upregulation. Cells pretreated with cadmium showed markedly enhanced invasiveness and this effect was partially abrogated by uPAR-neutralizing antibodies and by inhibitors of ERK-1/2, NF-κB, and AP-1. These results suggest that cadmium induces uPAR expression via ERK-1/2, NF-κB, and AP-1 signaling pathways and, in turn, stimulates cell invasiveness in human gastric cancer AGS cells.
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October 2014
Volume 45 Issue 4

Print ISSN: 1019-6439
Online ISSN:1791-2423

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APA
Khoi, P.N., Xia, Y., Lian, S., Kim, H.D., Kim, D.H., Joo, Y.E. ... Jung, Y.D. (2014). Cadmium induces urokinase-type plasminogen activator receptor expression and the cell invasiveness of human gastric cancer cells via the ERK-1/2, NF-κB, and AP-1 signaling pathways. International Journal of Oncology, 45, 1760-1768. https://doi.org/10.3892/ijo.2014.2558
MLA
Khoi, P. N., Xia, Y., Lian, S., Kim, H. D., Kim, D. H., Joo, Y. E., Chay, K., Kim, K. K., Jung, Y. D."Cadmium induces urokinase-type plasminogen activator receptor expression and the cell invasiveness of human gastric cancer cells via the ERK-1/2, NF-κB, and AP-1 signaling pathways". International Journal of Oncology 45.4 (2014): 1760-1768.
Chicago
Khoi, P. N., Xia, Y., Lian, S., Kim, H. D., Kim, D. H., Joo, Y. E., Chay, K., Kim, K. K., Jung, Y. D."Cadmium induces urokinase-type plasminogen activator receptor expression and the cell invasiveness of human gastric cancer cells via the ERK-1/2, NF-κB, and AP-1 signaling pathways". International Journal of Oncology 45, no. 4 (2014): 1760-1768. https://doi.org/10.3892/ijo.2014.2558