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PMID: 16027366 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, P.H.S.

Activation of beta-catenin by carcinogenic Helicobacter pylori.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 102 ·No. 30 ·2005-07-26 ·Pages 10646-51

Franco AT, Israel DA, Washington MK, Krishna U, Fox JG, Rogers AB, Neish AS, Collier-Hyams L, Perez-Perez GI, Hatakeyama M, Whitehead R, Gaus K, O'Brien DP, Romero-Gallo J, Peek RM

Abstract

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.

MeSH Terms
Adenocarcinoma/metabolism,microbiology Animals Antigens, Bacterial/metabolism,physiology Bacterial Proteins/metabolism,physiology Blotting, Western Enzyme-Linked Immunosorbent Assay Fluorescent Antibody Technique Gene Expression Regulation, Neoplastic Gerbillinae Helicobacter pylori/metabolism Humans Immunohistochemistry Luciferases Male Protein Transport/physiology Stomach Neoplasms/metabolism,microbiology beta Catenin/metabolism
Chemicals
Antigens, Bacterial Bacterial Proteins beta Catenin cagA protein, Helicobacter pylori Luciferases
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Franco Aime T
Division of Gastroenterology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-2279, USA.
Israel Dawn A
Washington Mary K
Krishna Uma
Fox James G
Rogers Arlin B
Neish Andrew S
Collier-Hyams Lauren
Perez-Perez Guillermo I
Hatakeyama Masanori
Whitehead Robert
Gaus Kristin
O'Brien Daniel P
Romero-Gallo Judith
Peek Richard M
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0504927102
Published
2005-07-26
Epub
2005-00-18
Pages
10646-51
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC1180811
Subset
IM
Grants
NCI NIH HHS · R01 CA077955 · United States
NCI NIH HHS · R29 CA077955 · United States
NIDDK NIH HHS · DK-58587 · United States
NCI NIH HHS · CA-77955 · United States
NCI NIH HHS · T32 CA009592 · United States
NIDDK NIH HHS · R01 DK058587 · United States
External Links
PubMed source DOI: 10.1073/pnas.0504927102 PMC Full Text View journal details
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