TitleH. pylori virulence factor CagA increases intestinal cell proliferation by Wnt pathway activation in a transgenic zebrafish model.
Publication TypeJournal Article
Year of Publication2013
AuthorsNeal, JT, Peterson, TS, Kent, ML, Guillemin, K
JournalDis Model Mech
Date Published2013 May
KeywordsAdenocarcinoma, Aging, Alleles, Animals, Animals, Genetically Modified, Antigens, Bacterial, Bacterial Proteins, beta Catenin, Cell Proliferation, Disease Models, Animal, Epithelium, Helicobacter Infections, Helicobacter pylori, Hyperplasia, Intestinal Mucosa, Intestinal Neoplasms, Intestines, Phosphorylation, Transcription Factor 4, Transcription Factors, Transgenes, Tumor Suppressor Protein p53, Virulence Factors, Wnt Signaling Pathway, Zebrafish, Zebrafish Proteins

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.

Alternate JournalDis Model Mech
PubMed ID23471915
PubMed Central IDPMC3634662
Grant ListR01 DK075667 / DK / NIDDK NIH HHS / United States
T32 GM007413 / GM / NIGMS NIH HHS / United States
HD22486 / HD / NICHD NIH HHS / United States
P01 HD022486 / HD / NICHD NIH HHS / United States
1R01DK075667 / DK / NIDDK NIH HHS / United States
T32 GM007759 / GM / NIGMS NIH HHS / United States