@article{1b7101186bb64e499648706e02582d82,
title = "A single-nucleotide polymorphism in Helicobacter pylori promotes gastric cancer development",
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.",
keywords = "53BP1, DNA double-strand breaks, gastric cancer, H. pylori, HtrA, NF-κB, PFGE, signaling, SNP, β-catenin",
author = "Irshad Sharafutdinov and Nicole Tegtmeyer and Bodo Linz and Manfred Rohde and Michael Vieth and Tay, {Alfred Chin Yen} and Binit Lamichhane and Tuan, {Vo Phuoc} and Fauzia, {Kartika Afrida} and Heinrich Sticht and Yoshio Yamaoka and Marshall, {Barry J.} and Steffen Backert",
note = "Funding Information: We thank Wilhelm Brill and Nina Rottmann for excellent technical assistance, Erin M. Schuman for the β-catenin-GFP construct, and FAU Erlangen-N{\"u}rnberg for “Open Access Publishing,” and the Japanese MEXT grants 18KK0266 and 19H03473 (Y.Y.). We also acknowledge the use of the Leica Stellaris 8 Microscope ( DFG grant number 441730715 ) at the Optical Imaging Centre Erlangen. Funding Information: We thank Wilhelm Brill and Nina Rottmann for excellent technical assistance, Erin M. Schuman for the β-catenin-GFP construct, and FAU Erlangen-N{\"u}rnberg for “Open Access Publishing,” and the Japanese MEXT grants 18KK0266 and 19H03473 (Y.Y.). We also acknowledge the use of the Leica Stellaris 8 Microscope (DFG grant number 441730715) at the Optical Imaging Centre Erlangen. S.B. conceptualized the study and wrote the manuscript. B. Linz conducted the genomic studies, N.T. performed the casein assays, infections, luciferase assays, and western blotting. M.R. did the EM studies and M.V. the biopsy analyses. I.S. performed all immunofluorescence experiments. A.C.-Y.T. B. Lamichhane, V.P.T. K.A.F. B.J.M. and Y.Y. isolated H. pylori from patients and performed whole-genome sequencing. H.S. conducted the 3D structural analyses of HtrA. All co-authors reviewed and edited the final manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2023 Elsevier Inc.",
year = "2023",
month = aug,
day = "9",
doi = "10.1016/j.chom.2023.06.016",
language = "English",
volume = "31",
pages = "1345--1358.e6",
journal = "Cell Host and Microbe",
issn = "1931-3128",
publisher = "Cell Press",
number = "8",
}
