Helicobacter pylori promote gastric cancer cells invasion through a NF-kappaB and COX-2-mediated pathway.
OBJECTIVE
To examine the effects of Helicobacter pylori (H pylori) infection on the invasiveness of gastric cancer cells, and to elucidate its mechanism.


METHODS
Gastric carcinoma cells, MKN-45, were incubated with CagA-positive H pylori, and cell invasion was determined by Matrigel analysis. The expression of matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEGF), and cyclooxygenase-2 (COX-2) were assessed by Western-blot analysis, and transcriptional activation of the COX-2 promoter was examined by measuring luciferase and beta-galactosidase activities. Lastly, the protein-DNA interaction was confirmed by an electrophoretic mobility shift assay.


RESULTS
The current studies showed that: (1) incubation of CagA-positive H pylori with MKN-45 cells significantly promotes gastric cancer cells invasion, and this effect is attenuated by pre-treatment with NS-398, a COX-2 inhibitor, or PDTC, a nuclear factor kappaB (NF-kappaB) inhibitor; (2) the induction of MKN-45 cells invasion by H pylori is associated with increases in COX-2, MMP-9, and VEGF protein expression, and co-incubation of NS-398 or PDTC significantly reduces these effects; (3) H pylori infection transactivates COX-2 promoter activity and increases the binding of NF-kappaB to this promoter.


CONCLUSIONS
Our data demonstrate that H pylori infection promotes gastric epithelial cells invasion by activating MMP-9 and VEGF expression. These effects appear to be mediated through a NF-kappaB and COX-2 mediated pathway, as COX-2 or NF-kappaB inhibitor significantly attenuate the invasiveness of gastric cancer cells and the expressions of MMP-9 and VEGF protein.
Wu
Chun-Ying
CY
Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taiwan, China.
Wang
Chau-Jong
CJ
Tseng
Chi-Chuan
CC
Chen
Hsiao-Ping
HP
Wu
Ming-Shing
MS
Lin
Jaw-Town
JT
Inoue
Hiroyasu
H
Chen
Gran-Hum
GH
D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2; D015972:Gene Expression Regulation, Neoplastic; D016481:Helicobacter Infections / Q000378:metabolism* / Q000473:pathology; D016480:Helicobacter pylori; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D008565:Membrane Proteins; D016328:NF-kappa B / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D008565:Membrane Proteins; D016328:NF-kappa B; D042461:Vascular Endothelial Growth Factor A; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020780:Matrix Metalloproteinase 9