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Effects of Helicobacter pylori CagA protein on the growth and survival of B lymphocytes, the origin of MALT lymphoma

Abstract

Helicobacter pylori (H. pylori) is a causative agent of gastrointestinal diseases such as atrophic gastritis and gastroduodenal ulcer. Infection of cagA-positive H. pylori is also associated with gastric carcinoma and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. The cagA gene product CagA is directly injected into the bacteria-attached host cells via the bacterial type IV secretion system. The translocated CagA deregulates intracellular signaling pathways and thereby initiates pathogenesis. In this work, we examined the biological effects of CagA on B cells, from which MALT lymphoma arises. Ectopic expression of CagA in interleukin 3-dependent B cells inhibited cell proliferation by suppressing the JAK-STAT signaling. CagA was also capable of preventing hydroxyurea-induced B-cell apoptosis through inhibiting p53 accumulation. In contrast to the effects of CagA in gastric epithelial cells, the observed CagA activities in B cells were independent of its tyrosine phosphorylation. Our results indicate that CagA possesses both phosphorylation-dependent and -independent activities in mammalian cells and that biological impacts of CagA depend on cell-type context. As a result of B-cell growth inhibition, CagA may diminish anti-H. pylori immune responses. Furthermore, CagA may play a role in the development of MALT lymphoma by impairing p53-dependent apoptosis.

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Acknowledgements

We thank Dr Yosuke Miura for technical help. We also thank members of the Hatakeyama Laboratory for their technical assistance and helpful discussions. This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan, and by a grant of the Virtual Research Institute of Aging of Nippon Boehringer Ingelheim.

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Correspondence to Masanori Hatakeyama.

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Umehara, S., Higashi, H., Ohnishi, N. et al. Effects of Helicobacter pylori CagA protein on the growth and survival of B lymphocytes, the origin of MALT lymphoma. Oncogene 22, 8337–8342 (2003). https://doi.org/10.1038/sj.onc.1207028

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