Helicobacter pylori strain-specific genotypes and modulation of the gastric epithelial cell cycle.
Helicobacter pylori cag+ strains enhance gastric epithelial cell proliferation and attenuate apoptosis in vivo, which may partially explain the increased risk of gastric cancer associated with these strains. The goals of this study were to identify specific H. pylori genes that regulate epithelial cell cycle events and determine whether these effects were dependent upon p53-mediated pathways. AGS gastric epithelial cells were cultured alone or in the presence of 21 clinical H. pylori isolates, H. pylori reference strain 60190, or its isogenic cagA-, picB-, vacA-, or picB-/vacA- derivatives. Coculture of H. pylori with AGS cells significantly decreased cell viability, an effect most prominent with cag+ strains (P < 0.001 versus cag-strains). cag+ strains significantly increased progression of AGS cells from G1 into G2-M at 6 h and enhanced apoptosis by 72 h. Compared with the parental 60190 strain, the picB- mutant attenuated cell cycle progression at 6 h (P < or = 0.05), and decreased apoptosis with enhanced AGS cell viability at 24 h (P < or = 0.04). The vacA- mutant decreased apoptosis and enhanced viability at later (48-72 h) time points (P < or = 0.05). Compared with the wild-type strain, the picB-/vacA- double mutant markedly attenuated apoptosis and increased cell viability at all time points (P < or = 0.05). Furthermore, cocolonization with H. pylori had no significant effect on expression of p53, p21, and MDM2. The diminished AGS cell viability, progression to G2-M, and apoptosis associated with cag+ H. pylori strains were dependent upon expression of vacA and genes within the cag pathogenicity island. These results may explain heterogeneity in levels of gastric epithelial cell proliferation and apoptosis found within H. pyloricolonized mucosa.
Peek
R M
RM
Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2279, USA. richard.peek@mcmail.vanderbilt.edu
Blaser
M J
MJ
Mays
D J
DJ
Forsyth
M H
MH
Cover
T L
TL
Song
S Y
SY
Krishna
U
U
Pietenpol
J A
JA
D017209:Apoptosis; D001426:Bacterial Proteins / Q000378:metabolism; D002453:Cell Cycle; D002470:Cell Survival; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis; D005753:Gastric Mucosa / Q000382:microbiology* / Q000473:pathology*; D005838:Genotype; D016481:Helicobacter Infections / Q000503:physiopathology; D016480:Helicobacter pylori / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D051736:Proto-Oncogene Proteins c-mdm2; D013045:Species Specificity; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
D001426:Bacterial Proteins; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009687:Nuclear Proteins; C103937:PicB protein, Helicobacter pylori; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C074689:VacA protein, Helicobacter pylori; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2