Activation of beta-catenin by carcinogenic Helicobacter pylori.
Persistent gastritis induced by Helicobacter pylori is the strongest known risk factor for adenocarcinoma of the distal stomach, yet only a fraction of colonized persons ever develop gastric cancer. The H. pylori cytotoxin-associated gene (cag) pathogenicity island encodes a type IV secretion system that delivers the bacterial effector CagA into host cells after bacterial attachment, and cag+ strains augment gastric cancer risk. A host effector that is aberrantly activated in gastric cancer precursor lesions is beta-catenin, and activation of beta-catenin leads to targeted transcriptional up-regulation of genes implicated in carcinogenesis. We report that in vivo adaptation endowed an H. pylori strain with the ability to rapidly and reproducibly induce gastric dysplasia and adenocarcinoma in a rodent model of gastritis. Compared with its parental noncarcinogenic isolate, the oncogenic H. pylori strain selectively activates beta-catenin in model gastric epithelia, which is dependent on translocation of CagA into host epithelial cells. Beta-catenin nuclear accumulation is increased in gastric epithelium harvested from gerbils infected with the H. pylori carcinogenic strain as well as from persons carrying cag+ vs. cag- strains or uninfected persons. These results indicate that H. pylori-induced dysregulation of beta-catenin-dependent pathways may explain in part the augmentation in the risk of gastric cancer conferred by this pathogen.
Franco
Aime T
AT
Division of Gastroenterology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-2279, USA.
Israel
Dawn A
DA
Washington
Mary K
MK
Krishna
Uma
U
Fox
James G
JG
Rogers
Arlin B
AB
Neish
Andrew S
AS
Collier-Hyams
Lauren
L
Perez-Perez
Guillermo I
GI
Hatakeyama
Masanori
M
Whitehead
Robert
R
Gaus
Kristin
K
O'Brien
Daniel P
DP
Romero-Gallo
Judith
J
Peek
Richard M
RM
D000230:Adenocarcinoma / Q000378:metabolism / Q000382:microbiology*; D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism* / Q000502:physiology; D001426:Bacterial Proteins / Q000378:metabolism* / Q000502:physiology; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D005849:Gerbillinae; D016480:Helicobacter pylori / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008156:Luciferases; D008297:Male; D021381:Protein Transport / Q000502:physiology; D013274:Stomach Neoplasms / Q000378:metabolism / Q000382:microbiology*; D051176:beta Catenin / Q000378:metabolism*
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D051176:beta Catenin; C080866:cagA protein, Helicobacter pylori; D008156:Luciferases