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H. pylori virulence factor CagA increases intestinal cell proliferation by Wnt pathway activation in a transgenic zebrafish model.
- Source :
-
Disease models & mechanisms [Dis Model Mech] 2013 May; Vol. 6 (3), pp. 802-10. Date of Electronic Publication: 2013 Mar 01. - Publication Year :
- 2013
-
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.
- Subjects :
- Adenocarcinoma pathology
Aging pathology
Alleles
Animals
Animals, Genetically Modified
Cell Proliferation
Disease Models, Animal
Epithelium metabolism
Epithelium microbiology
Epithelium pathology
Helicobacter Infections metabolism
Helicobacter Infections microbiology
Helicobacter Infections pathology
Hyperplasia
Intestinal Mucosa metabolism
Intestinal Neoplasms metabolism
Intestinal Neoplasms pathology
Phosphorylation
Transcription Factor 4
Transcription Factors metabolism
Transgenes
Tumor Suppressor Protein p53 metabolism
Zebrafish Proteins metabolism
beta Catenin metabolism
Antigens, Bacterial metabolism
Bacterial Proteins metabolism
Helicobacter pylori pathogenicity
Intestines microbiology
Intestines pathology
Virulence Factors metabolism
Wnt Signaling Pathway
Zebrafish microbiology
Subjects
Details
- Language :
- English
- ISSN :
- 1754-8411
- Volume :
- 6
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Disease models & mechanisms
- Publication Type :
- Academic Journal
- Accession number :
- 23471915
- Full Text :
- https://doi.org/10.1242/dmm.011163