Kiss-1 suppresses MMP-9 expression by activating p38 MAP kinase in human stomach cancer.
Kiss-1 has been identified as a putative metastasis suppressor gene in various human malignancies. However, there is little information about its possible role in gastric carcinoma. In this study, we determined whether the Kiss-1 gene negatively regulates MMP-9 expression. cDNA microarray technology was used to identify the genes associated with metastasis by hepatocyte growth factor (HGF) in the gastric cancer cell lines, NUGC-3 and MKN-28. The levels of Kiss-1 RNA and protein were confirmed to be upregulated in HGF-treated gastric cancer cells. HGF induced Kiss-1 and MMP-9 production in a dose-dependent manner. In order to investigate roles of HGF signaling in tumor progression and metastasis, we measured effects of a specific MEK1 inhibitor (PD 098059) and a p38 kinase inhibitor (SB 203580) on HGF-mediated cell proliferation and MMP-9. Pretreatment with PD 098059 reduced MMP-9 and HGF-mediated cell proliferation, but increased Kiss-I expression. In contrast, SB 203580 pretreatment enhanced MMP-9 and cell prolifera-tion, but decreased Kiss-1 expression. Cotreatment of PD098059 and SB203580 increased the p38 phosphorylation stimulated by HGF. These results suggest that the HGF-mediated Kiss-1 overexpression is regulated mainly by the p38 activation and, furthermore, the activation of ERK might affect HGF-mediated Kiss-1 expression indirectly by the regulation of p38 kinase. Consistent with this result, p38 phosphorylation was strongly repressed by the knock-down of Kiss-1. Downregulation of Kiss-1 using Kiss-1 shRNA also increased in vitro cell invasion. In conclusion, Kiss-1 suppresses MMP-9 expression by activating the p38 MAP kinase signaling pathway.
Lee
Kyung Hee
KH
Department of Hematology-Oncology, College of Medicine, Yeungnam University, Daegu, Korea.
Kim
Jae-Ryong
JR
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D004789:Enzyme Activation; D005419:Flavonoids / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D059648:Kisspeptins; D020935:MAP Kinase Signaling System; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D011725:Pyridines / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
D005419:Flavonoids; D007093:Imidazoles; C106628:KISS1 protein, human; D059648:Kisspeptins; D011725:Pyridines; D025521:Tumor Suppressor Proteins; D017228:Hepatocyte Growth Factor; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one