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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.
Int J Oncol. 2014 Oct; 45(4):1760-8.IJ

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.

Authors+Show Affiliations

Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-190, Republic of Korea.Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-190, Republic of Korea.Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-190, Republic of Korea.Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-190, Republic of Korea.Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-190, Republic of Korea.Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-190, Republic of Korea.Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-190, Republic of Korea.Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-190, Republic of Korea.Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-190, Republic of Korea.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

25069788

Citation

Khoi, Pham Ngoc, et al. "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, vol. 45, no. 4, 2014, pp. 1760-8.
Khoi PN, Xia Y, Lian S, et al. 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. Int J Oncol. 2014;45(4):1760-8.
Khoi, P. N., Xia, Y., Lian, S., Kim, H. D., Kim, D. H., Joo, Y. E., Chay, K. O., Kim, K. K., & 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(4), 1760-8. https://doi.org/10.3892/ijo.2014.2558
Khoi PN, et al. 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. Int J Oncol. 2014;45(4):1760-8. PubMed PMID: 25069788.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Khoi,Pham Ngoc, AU - Xia,Yong, AU - Lian,Sen, AU - Kim,Ho Dong, AU - Kim,Do Hyun, AU - Joo,Young Eun, AU - Chay,Kee-Oh, AU - Kim,Kyung Keun, AU - Jung,Young Do, Y1 - 2014/07/22/ PY - 2014/05/08/received PY - 2014/07/03/accepted PY - 2014/7/30/entrez PY - 2014/7/30/pubmed PY - 2015/6/10/medline SP - 1760 EP - 8 JF - International journal of oncology JO - Int J Oncol VL - 45 IS - 4 N2 - 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. SN - 1791-2423 UR - https://www.unboundmedicine.com/medline/citation/25069788/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_ L2 - http://www.spandidos-publications.com/ijo/45/4/1760 DB - PRIME DP - Unbound Medicine ER -