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PMID: 23471915 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

H. pylori virulence factor CagA increases intestinal cell proliferation by Wnt pathway activation in a transgenic zebrafish model.

Disease models & mechanisms ·Vol. 6 ·No. 3 ·2013-05-00 ·Pages 802-10

Neal JT, Peterson TS, Kent ML, Guillemin K

Abstract

Infection with Helicobacter pylori is a major risk factor for the development of gastric cancer, and infection with strains carrying the virulence factor CagA significantly increases this risk. To investigate the mechanisms by which CagA promotes carcinogenesis, we generated transgenic zebrafish expressing CagA ubiquitously or in the anterior intestine. Transgenic zebrafish expressing either the wild-type or a phosphorylation-resistant form of CagA exhibited significantly increased rates of intestinal epithelial cell proliferation and showed significant upregulation of the Wnt target genes cyclinD1, axin2 and the zebrafish c-myc ortholog myca. Coexpression of CagA with a loss-of-function allele encoding the β-catenin destruction complex protein Axin1 resulted in a further increase in intestinal proliferation. Coexpression of CagA with a null allele of the key β-catenin transcriptional cofactor Tcf4 restored intestinal proliferation to wild-type levels. These results provide in vivo evidence of Wnt pathway activation by CagA downstream of or in parallel to the β-catenin destruction complex and upstream of Tcf4. Long-term transgenic expression of wild-type CagA, but not the phosphorylation-resistant form, resulted in significant hyperplasia of the adult intestinal epithelium. We further utilized this model to demonstrate that oncogenic cooperation between CagA and a loss-of-function allele of p53 is sufficient to induce high rates of intestinal small cell carcinoma and adenocarcinoma, establishing the utility of our transgenic zebrafish model in the study of CagA-associated gastrointestinal cancers.

MeSH Terms
Adenocarcinoma/pathology Aging/pathology Alleles Animals Animals, Genetically Modified Antigens, Bacterial/metabolism Bacterial Proteins/metabolism Cell Proliferation Disease Models, Animal Epithelium/metabolism,microbiology,pathology Helicobacter Infections/metabolism,microbiology,pathology Helicobacter pylori/pathogenicity Hyperplasia Intestinal Mucosa/metabolism Intestinal Neoplasms/metabolism,pathology Intestines/microbiology,pathology Phosphorylation Transcription Factor 4 Transcription Factors/metabolism Transgenes Tumor Suppressor Protein p53/metabolism Virulence Factors/metabolism Wnt Signaling Pathway Zebrafish/microbiology Zebrafish Proteins/metabolism beta Catenin/metabolism
Chemicals
Antigens, Bacterial Bacterial Proteins Tcf4 protein, zebrafish Transcription Factor 4 Transcription Factors Tumor Suppressor Protein p53 Virulence Factors Zebrafish Proteins beta Catenin cagA protein, Helicobacter pylori
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Neal James T
Institute of Molecular Biology, University of Oregon, Eugene, OR 97403, USA.
Peterson Tracy S
Kent Michael L
Guillemin Karen
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Article Info
Journal
Disease models & mechanisms
Abbr.
Dis Model Mech
ISSN
1754-8411
DOI
10.1242/dmm.011163
Published
2013-05-00
Epub
2013-00-01
Pages
802-10
Language
English
Region
England
NLM ID
101483332
PMCID
PMC3634662
Subset
IM
Grants
NICHD NIH HHS · HD22486 · United States
NICHD NIH HHS · P01 HD022486 · United States
NIDDK NIH HHS · 1R01DK075667 · United States
NIGMS NIH HHS · T32 GM007759 · United States
NIDDK NIH HHS · R01 DK075667 · United States
NIGMS NIH HHS · T32 GM007413 · United States
External Links
PubMed source DOI: 10.1242/dmm.011163 PMC Full Text View journal details
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