Rm. Peek et al., Helicobacter pylori strain-specific genotypes and modulation of the gastric epithelial cell cycle, CANCER RES, 59(24), 1999, pp. 6124-6131
Helicobacter pylori cag(+) strains enhance gastric epithelial cell prolifer
ation and attenuate apoptosis in vivo, which may partially explain the incr
eased risk of gastric cancer associated with these strains. The goals of th
is 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 stra
in 60190, or its isogenic cagA(-), picB(-), vacA(-), or picB(-)/vacA(-) der
ivatives. Coculture of H. pylori with AGS cells significantly decreased cel
l viability, an effect most prominent with cag(+) strains (P < 0.001 versus
cag(-) strains). cag(+) strains significantly increased progression of AGS
cells from G(1) into G(2)-M at 6 h and enhanced apoptosis by 72 h. Compare
d with the parental 60190 strain, the picB(-) mutant attenuated cell cycle
progression at 6 h (P less than or equal to 0.05), and decreased apoptosis
with enhanced AGS cell viability at 24 h (P less than or equal to 0.04). Th
e vacA(-) mutant decreased apoptosis and enhanced viability at later (48-72
h) time points (P less than or equal to 0.05). Compared with the wild-type
strain, the picB(-)/vacA(-) double mutant markedly attenuated apoptosis an
d increased cell viability at all time points (P less than or equal to 0.05
), Furthermore, cocolonization with H. pylori had no significant effect on
expression of p53, p21, and MDM2. The diminished AGS cell viability, progre
ssion to G(2)-M, and apoptosis associated with cag(+) H. pylori strains wer
e dependent upon expression of vacA and genes within the cag pathogenicity
island. These results may explain heterogeneity in levels of gastric epithe
lial cell proliferation and apoptosis found within H. pylori-colonized muco
sa.