A single-nucleotide polymorphism in Helicobacter pylori promotes gastric cancer development

Irshad Sharafutdinov, Nicole Tegtmeyer, Bodo Linz, Manfred Rohde, Michael Vieth, Alfred Chin Yen Tay, Binit Lamichhane, Vo Phuoc Tuan, Kartika Afrida Fauzia, Heinrich Sticht, Yoshio Yamaoka, Barry J. Marshall, Steffen Backert

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

Abstract

Single-nucleotide polymorphisms (SNPs) in various human genes are key factors in carcinogenesis. However, whether SNPs in bacterial pathogens are similarly crucial in cancer development is unknown. Here, we analyzed 1,043 genomes of the stomach pathogen Helicobacter pylori and pinpointed a SNP in the serine protease HtrA (position serine/leucine 171) that significantly correlates with gastric cancer. Our functional studies reveal that the 171S-to-171L mutation triggers HtrA trimer formation and enhances proteolytic activity and cleavage of epithelial junction proteins occludin and tumor-suppressor E-cadherin. 171L-type HtrA, but not 171S-HtrA-possessing H. pylori, inflicts severe epithelial damage, enhances injection of oncoprotein CagA into epithelial cells, increases NF-κB-mediated inflammation and cell proliferation through nuclear accumulation of β-catenin, and promotes host DNA double-strand breaks, collectively triggering malignant changes. These findings highlight the 171S/L HtrA mutation as a unique bacterial cancer-associated SNP and as a potential biomarker for risk predictions in H. pylori infections.

Original languageEnglish
Pages (from-to)1345-1358.e6
JournalCell Host and Microbe
Volume31
Issue number8
DOIs
Publication statusPublished - 9 Aug 2023

Keywords

  • 53BP1
  • DNA double-strand breaks
  • H. pylori
  • HtrA
  • NF-κB
  • PFGE
  • SNP
  • gastric cancer
  • signaling
  • β-catenin

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