Helicobacter pylori CagA promotes Snail-mediated epithelial–mesenchymal transition by reducing GSK-3 activity

Da-Gyum Lee, Hyun Sil Kim, Yeo Song Lee, Shin Kim, So Young Cha, Ichiro Ota, Nam Hee Kim, Yong Hoon Cha, Dong Hyun Yang, Yoonmi Lee, Gyeong-Ju Park, Jong In Yook () and Yong Chan Lee ()
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Da-Gyum Lee: Yonsei University College of Medicine
Hyun Sil Kim: Oral Cancer Research Institute, Yonsei University College of Dentistry
Yeo Song Lee: Yonsei University College of Medicine
Shin Kim: Yonsei University College of Medicine
So Young Cha: Oral Cancer Research Institute, Yonsei University College of Dentistry
Ichiro Ota: Nara Medical University
Nam Hee Kim: Oral Cancer Research Institute, Yonsei University College of Dentistry
Yong Hoon Cha: Oral Cancer Research Institute, Yonsei University College of Dentistry
Dong Hyun Yang: Oral Cancer Research Institute, Yonsei University College of Dentistry
Yoonmi Lee: Oral Cancer Research Institute, Yonsei University College of Dentistry
Gyeong-Ju Park: The School of Dentistry, Dankook University
Jong In Yook: Oral Cancer Research Institute, Yonsei University College of Dentistry
Yong Chan Lee: Yonsei University College of Medicine

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: Abstract Cytotoxin-associated gene A (CagA) is an oncoprotein and a major virulence factor of H. pylori. CagA is delivered into gastric epithelial cells via a type IV secretion system and causes cellular transformation. The loss of epithelial adhesion that accompanies the epithelial–mesenchymal transition (EMT) is a hallmark of gastric cancer. Although CagA is a causal factor in gastric cancer, the link between CagA and the associated EMT has not been elucidated. Here, we show that CagA induces the EMT by stabilizing Snail, a transcriptional repressor of E-cadherin expression. Mechanistically we show that CagA binds GSK-3 in a manner similar to Axin and causes it to shift to an insoluble fraction, resulting in reduced GSK-3 activity. We also find that the level of Snail protein is increased in H. pylori infected epithelium in clinical samples. These results suggest that H. pylori CagA acts as a pathogenic scaffold protein that induces a Snail-mediated EMT via the depletion of GSK-3.

Date: 2014
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DOI: 10.1038/ncomms5423

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