Helicobacter pylori induces gastric epithelial cell invasion in a c-Met and type IV secretion system-dependent manner.
Helicobacter pylori interacts with gastric epithelial cells, activating signaling pathways important for carcinogenesis. In this study we examined the role of H. pylori on cell invasion and the molecular mechanisms underlying this process. The relevance of H. pylori cag pathogenicity island-encoded type IV secretion system (T4SS), CagA, and VacA for cell invasion was also investigated. We found that H. pylori induces AGS cell invasion in collagen type I and in Matrigel invasion assays. H. pylori-induced cell invasion requires the direct contact between bacteria and cancer cells. H. pylori-mediated cell invasion was dependent on the activation of the c-Met receptor and on increased MMP-2 and MMP-9 activity. The abrogation of the c-Met receptor using the specific NK4 inhibitor or the silencing of c-Met expression with small interference RNA suppressed both cell invasion and MMP activity. Studies with different H. pylori strains revealed that cell invasion, c-Met tyrosine phosphorylation, and increased MMP-2 and MMP-9 activity were all dependent on the presence of a functional bacterial T4SS, but not on VacA cytotoxicity. Our findings demonstrate that H. pylori strains with a functional T4SS stimulate gastric epithelial cell invasion through a c-Met-dependent signaling pathway that comprises an increase in MMP-2 and MMP-9 activity.
Oliveira
Maria J
MJ
Institute of Molecular Pathology and Immunology, University of Porto (IPATIMUP), Portugal, and the Laboratory of Experimental Cancerology, Ghent University Hospital, Belgium.
Costa
Ana C
AC
Costa
Angela M
AM
Henriques
Lara
L
Suriano
Gianpaolo
G
Atherton
John C
JC
Machado
Jose C
JC
Carneiro
Fatima
F
Seruca
Raquel
R
Mareel
Marc
M
Leroy
Ancy
A
Figueiredo
Ceu
C
D000942:Antigens, Bacterial / Q000378:metabolism; D001426:Bacterial Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology*; D044404:Genomic Islands / Q000502:physiology; D016480:Helicobacter pylori / Q000378:metabolism*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D013270:Stomach / Q000166:cytology
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C074689:VacA protein, Helicobacter pylori; C080866:cagA protein, Helicobacter pylori; D019859:Proto-Oncogene Proteins c-met; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9