title: MSP-induced RON activation upregulates uPAR expression and cell invasiveness via MAPK, AP-1 and NF-κB signals in gastric cancer cells.
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.affiliation: Research Institute of Medical Sciences, Chonnam National University Medical School, Kwangju 501-190, Korea.
authors.forename: Jung Sun
authors.initials: JS
authors.lastname: Park
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Park
authors.forename: Pham Ngoc
authors.initials: PN
authors.lastname: Khoi
authors.forename: Young Eun
authors.initials: YE
authors.lastname: Joo
authors.forename: Young Do
authors.initials: YD
authors.lastname: Jung
mesh_terms: D045744:Cell Line, Tumor; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009361:Neoplasm Invasiveness; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics*; D015398:Signal Transduction / Q000502:physiology*; D013274:Stomach Neoplasms / Q000473:pathology*; D018808:Transcription Factor AP-1 / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D011518:Proto-Oncogene Proteins; D055293:Receptors, Urokinase Plasminogen Activator; D018808:Transcription Factor AP-1; C082332:macrophage stimulating protein; D017228:Hepatocyte Growth Factor; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases