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, Yong Chan Lee

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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.

Original languageEnglish
Article number4423
JournalNature communications
Volume5
DOIs
Publication statusPublished - 2014 Jul 23

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All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Lee, D. G., Kim, H. S., Lee, Y. S., Kim, S., Cha, S. Y., Ota, I., Kim, N. H., Cha, Y. H., Yang, D. H., Lee, Y., Park, G. J., Yook, J. I., & Lee, Y. C. (2014). Helicobacter pylori CagA promotes Snail-mediated epithelial-mesenchymal transition by reducing GSK-3 activity. Nature communications, 5, [4423]. https://doi.org/10.1038/ncomms5423