Helicobacter pylori cytotoxin-associated gene A activates the signal transducer and activator of transcription 3 pathway in vitro and in vivo.
Persistent infection with Helicobacter pylori confers an increased risk for the development of gastric cancer. However, the exact mechanisms whereby this bacterium causes carcinogenesis have not been completely elucidated. Recent evidence indicates that aberrant activation of the signal transducers and activators of transcription 3 (STAT3) signaling pathway may play a role in gastric carcinogenesis. Therefore, we hypothesized that H. pylori infection modulates STAT3 signaling, favoring gastric cancer development. In epithelial cells infected with H. pylori, STAT3 was activated, as assessed by immunoblotting for phosphorylated STAT3, immunofluorescence of translocated STAT3, fluorescence recovery after photobleaching, and luciferase activation in transfected cells. Activation was dependent on translocation but not phosphorylation of cytotoxin-associated gene A (CagA) in host cells. Activation seemed to be receptor-mediated because preincubation of cells with the interleukin-6 (IL-6) receptor superantagonist sant7 or inhibition of gp130 by a monoclonal antibody prevented H. pylori-mediated STAT3 activation. However, activation was not related to autocrine activation by IL-6 or IL-11. CagA+ wild-type H. pylori, but not the noncarcinogenic cagA- mutant, activated STAT3 in gastric epithelial cells in vivo in the gerbil model of H. pylori-mediated gastric carcinogenesis. Collectively, these results indicate that H. pylori CagA activates the STAT3 signaling pathway in vitro and in vivo, providing a potential mechanism by which chronic H. pylori infection promotes the development of gastric cancer.
Bronte-Tinkew
Dana M
DM
Department of Pediatrics and Physiology, University of Toronto, Toronto, Canada.
Terebiznik
Mauricio
M
Franco
Aime
A
Ang
Michelle
M
Ahn
Diane
D
Mimuro
Hitomi
H
Sasakawa
Chihiro
C
Ropeleski
Mark J
MJ
Peek
Richard M
RM
Jones
Nicola L
NL
D000230:Adenocarcinoma / Q000378:metabolism / Q000382:microbiology; D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D005849:Gerbillinae; D006367:HeLa Cells; D016481:Helicobacter Infections / Q000235:genetics / Q000378:metabolism; D016480:Helicobacter pylori / Q000378:metabolism*; D006801:Humans; D008297:Male; D010766:Phosphorylation; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000378:metabolism / Q000382:microbiology; D014158:Transcription, Genetic; D014443:Tyrosine / Q000378:metabolism
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C080866:cagA protein, Helicobacter pylori; D050822:Cytokine Receptor gp130; D014443:Tyrosine