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Helicobacter pylori infection triggers aberrant expression of activation-induced cytidine deaminase in gastric epithelium

Nature Medicine volume 13, pages 470–476 (2007)Cite this article

Abstract

Infection with Helicobacter pylori (H. pylori) is a risk factor for the development of gastric cancer. Here we show that infection of gastric epithelial cells with 'cag' pathogenicity island (cagPAI)-positive H. pylori induced aberrant expression of activation-induced cytidine deaminase (AID), a member of the cytidine-deaminase family that acts as a DNA- and RNA-editing enzyme, via the IκB kinase–dependent nuclear factor-κB activation pathway. H. pylori–mediated upregulation of AID resulted in the accumulation of nucleotide alterations in the TP53 tumor suppressor gene in gastric cells in vitro. Our findings provide evidence that aberrant AID expression caused by H. pylori infection might be a mechanism of mutation accumulation in the gastric mucosa during H. pylori–associated gastric carcinogenesis.

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Figure 1: Infection with cagPAI-positive H. pylori induces endogenous AID expression in gastric epithelial cells.
Figure 2: H. pylori–induced AID expression is mediated by NF-κB signaling.
Figure 3: AID expression is regulated by NF-κB signaling in gastric epithelial cells.
Figure 4: Immunohistochemical analysis of AID expression in 84 human gastric tissue specimens, including H. pylori–positive chronic gastritis (n = 35) and gastric cancer (n = 27), H. pylori-negative gastritis (n = 11) and gastric cancer (n = 2), and normal gastric mucosa lacking H. pylori infection (n = 9).

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Acknowledgements

We thank J.C. Weill (Faculte de Medecine Necker-Enfants Malades) for AID-deficient BL2 cells; A. Nomura, S. Sato and Y. Sakai (Kyoto University) for gastric tissue specimens; and H. Haga (Kyoto University) for assistance in the staining of H. pylori. This study was supported by a grant-in-aid for Scientific Research from the Japan Society for the Promotion of Science (15209024, 16790378 and 17002015).

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Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, 606-8507, Kyoto, Japan

    Yuko Matsumoto, Hiroyuki Marusawa, Yoko Endo, Tadayuki Kou, Toshiyuki Morisawa & Tsutomu Chiba

  2. Evolutionary Medicine, Shiga Medical Center Research Institute, 5-4-30, Moriyama, 524-8524, Shiga, Japan

    Kazuo Kinoshita

  3. Frontier Medical Science in Gastroenterology, International Center for Medical Research and Treatment, Kobe University School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, 650-0017, Kobe, Japan

    Takeshi Azuma

  4. Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, 606-8501, Kyoto, Japan

    Il-Mi Okazaki & Tasuku Honjo

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  1. Yuko Matsumoto
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Contributions

Y.M. conducted all the experiments except the analyses of Ig gene, and contributed to manuscript preparations. H.M. designed the study, supervised the project and contributed to manuscript preparations. K.K. performed the analyses of Ig gene, supervised the project and contributed to manuscript preparations. Y.E. worked on in vitro analyses related to NF-κB signaling. T.K. collected human samples and conducted analyses on them. T.M. analysed the transgenic mice. T.A. generated the isogenic cagE-knockout mutant of H. pylori. I.-M.O. generated and analysed the transgenic mice. T.H. and T.C. supervised the project and contributed to manuscript preparations.

Corresponding author

Correspondence to Tsutomu Chiba.

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Supplementary information

Supplementary Fig. 1

CagPAI-positive H. pylori infection induces morphologic changes in AGS gastric epithelial cells. (PDF 546 kb)

Supplementary Fig. 2

Detection of variable (V)-region gene rearrangement of the Ig gene. (PDF 255 kb)

Supplementary Fig. 3

Treatment with NF-κB signaling regulators did not affect the expression levels of transcripts encoding the cell cycle regulators cyclin D and E in gastric epithelial cells. (PDF 160 kb)

Supplementary Fig. 4

AID-induced mutagenesis in cancer-related genes in association with H. pylori infection. (PDF 155 kb)

Supplementary Fig. 5

AID induction and Trp53 mutation frequencies in wild type mice after H. pylori infection. (PDF 350 kb)

Supplementary Fig. 6

Immunohistochemical analysis of AID expression in H. pylori-positive human gastric mucosa. (PDF 1104 kb)

Supplementary Table 1

TP53 mutation frequencies in human gastric cancers, gastritis and normal mucosa in association with AICDA expression levels. (PDF 93 kb)

Supplementary Table 2

The oligonucleotide primers used in this study. (PDF 73 kb)

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Matsumoto, Y., Marusawa, H., Kinoshita, K. et al. Helicobacter pylori infection triggers aberrant expression of activation-induced cytidine deaminase in gastric epithelium. Nat Med 13, 470–476 (2007). https://doi.org/10.1038/nm1566

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