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MSP-induced RON activation upregulates uPAR expression and cell invasiveness via MAPK, AP-1 and NF-κB signals in gastric cancer cells.
Carcinogenesis. 2011 Feb; 32(2):175-81.C

Abstract

Overexpression of recepteur d'Origine nantais (RON) and urokinase plasminogen activator receptor (uPAR) have been observed in human gastric cancers. However, the interaction between RON and uPAR in gastric cancer is unclear. The present study investigated the effect of macrophage-stimulating protein (MSP, the RON ligand) on uPAR expression and the underlying signal pathways in human gastric cancer AGS cells. uPAR messenger RNA expression was induced by MSP in a time- and concentration-dependent manner. MSP also induced uPAR promoter activity. The introduction of RON-specific small interfering RNA (siRNA) significantly affected the MSP-induced uPAR transcription. Deleted and site-directed mutagenesis studies demonstrated the involvement of the binding sites of transcription factor nuclear factor-kappaB (NF-κB) and activator protein (AP)-1 in the MSP-induced uPAR expression. Studies with expression vectors encoding mutated-type NF-κB signaling molecules and AP-1 decoy confirmed that NF-κB and AP-1 were essential for the MSP-induced uPAR expression. In addition, MSP induced the activation of extracellular signal-regulated kinase-1/2 (Erk-1/2), c-Jun amino terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). Dominant-negative mutants (K97M and TAM67) and specific inhibitors of Erk-1/2 and JNK were able to suppress the MSP-induced uPAR expression. AGS cells pretreated with MSP showed a remarkably enhanced invasiveness, which was partially abrogated by siRNA-targeted RON and uPAR-neutralizing antibodies. The above results suggest that MSP induces uPAR expression via MAPK, AP-1 and NF-κB 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, Kwangju 501-190, Korea.No 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

21081472

Citation

Park, Jung Sun, et al. "MSP-induced RON Activation Upregulates uPAR Expression and Cell Invasiveness Via MAPK, AP-1 and NF-κB Signals in Gastric Cancer Cells." Carcinogenesis, vol. 32, no. 2, 2011, pp. 175-81.
Park JS, Park JH, Khoi PN, et al. MSP-induced RON activation upregulates uPAR expression and cell invasiveness via MAPK, AP-1 and NF-κB signals in gastric cancer cells. Carcinogenesis. 2011;32(2):175-81.
Park, J. S., Park, J. H., Khoi, P. N., Joo, Y. E., & Jung, Y. D. (2011). MSP-induced RON activation upregulates uPAR expression and cell invasiveness via MAPK, AP-1 and NF-κB signals in gastric cancer cells. Carcinogenesis, 32(2), 175-81. https://doi.org/10.1093/carcin/bgq241
Park JS, et al. MSP-induced RON Activation Upregulates uPAR Expression and Cell Invasiveness Via MAPK, AP-1 and NF-κB Signals in Gastric Cancer Cells. Carcinogenesis. 2011;32(2):175-81. PubMed PMID: 21081472.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - MSP-induced RON activation upregulates uPAR expression and cell invasiveness via MAPK, AP-1 and NF-κB signals in gastric cancer cells. AU - Park,Jung Sun, AU - Park,Ji Hye, AU - Khoi,Pham Ngoc, AU - Joo,Young Eun, AU - Jung,Young Do, Y1 - 2010/11/16/ PY - 2010/11/18/entrez PY - 2010/11/18/pubmed PY - 2011/3/8/medline SP - 175 EP - 81 JF - Carcinogenesis JO - Carcinogenesis VL - 32 IS - 2 N2 - Overexpression of recepteur d'Origine nantais (RON) and urokinase plasminogen activator receptor (uPAR) have been observed in human gastric cancers. However, the interaction between RON and uPAR in gastric cancer is unclear. The present study investigated the effect of macrophage-stimulating protein (MSP, the RON ligand) on uPAR expression and the underlying signal pathways in human gastric cancer AGS cells. uPAR messenger RNA expression was induced by MSP in a time- and concentration-dependent manner. MSP also induced uPAR promoter activity. The introduction of RON-specific small interfering RNA (siRNA) significantly affected the MSP-induced uPAR transcription. Deleted and site-directed mutagenesis studies demonstrated the involvement of the binding sites of transcription factor nuclear factor-kappaB (NF-κB) and activator protein (AP)-1 in the MSP-induced uPAR expression. Studies with expression vectors encoding mutated-type NF-κB signaling molecules and AP-1 decoy confirmed that NF-κB and AP-1 were essential for the MSP-induced uPAR expression. In addition, MSP induced the activation of extracellular signal-regulated kinase-1/2 (Erk-1/2), c-Jun amino terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). Dominant-negative mutants (K97M and TAM67) and specific inhibitors of Erk-1/2 and JNK were able to suppress the MSP-induced uPAR expression. AGS cells pretreated with MSP showed a remarkably enhanced invasiveness, which was partially abrogated by siRNA-targeted RON and uPAR-neutralizing antibodies. The above results suggest that MSP induces uPAR expression via MAPK, AP-1 and NF-κB signaling pathways and, in turn, stimulates cell invasiveness in human gastric cancer AGS cells. SN - 1460-2180 UR - https://www.unboundmedicine.com/medline/citation/21081472/MSP_induced_RON_activation_upregulates_uPAR_expression_and_cell_invasiveness_via_MAPK_AP_1_and_NF_κB_signals_in_gastric_cancer_cells_ DB - PRIME DP - Unbound Medicine ER -