Abstract
Helicobacter pylori CagA is the first and only bacterial oncoprotein etiologically associated with human cancer. Upon delivery into gastric epithelial cells via bacterial type IV secretion, CagA acts as a pathogenic/pro-oncogenic scaffold that interacts with and functionally perturbs multiple host proteins such as pro-oncogenic SHP2 phosphatase and polarity-regulating kinase PAR1b/MARK2. Although H. pylori infection is established during early childhood, gastric cancer generally develops in elderly individuals, indicating that oncogenic CagA activity is effectively counteracted at a younger age. Moreover, the eradication of cagA-positive H. pylori cannot cure established gastric cancer, indicating that H. pylori CagA-triggered gastric carcinogenesis proceeds via a hit-and-run mechanism. In addition to its direct oncogenic action, CagA induces BRCAness, a cellular status characterized by replication fork destabilization and loss of error-free homologous recombination-mediated DNA double-strand breaks (DSBs) by inhibiting cytoplasmic-to-nuclear localization of the BRCA1 tumor suppressor. This causes genomic instability that leads to the accumulation of excess mutations in the host cell genome, which may underlie hit-and-run gastric carcinogenesis. The close connection between CagA and BRCAness was corroborated by a recent large-scale case–control study that revealed that the risk of gastric cancer in individuals carrying pathogenic variants of genes that induce BRCAness (such as BRCA1 and BRCA2) dramatically increases upon infection with cagA-positive H. pylori. Accordingly, CagA-mediated BRCAness plays a crucial role in the development of gastric cancer in conjunction with the direct oncogenic action of CagA.
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Acknowledgements
This work was supported by Grant-in-Aids for Scientific Research from Japan Society for the Promotion of Science (JSPS) to M.H. (16H06373 and 21H04804) and by Project for Cancer Research and Therapeutic Evolution (P-CREATE) from Japan Agency for Medical Research and Development (AMED), Japan, to M.H. (160200000291).
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Hatakeyama, M. (2023). Impact of the Helicobacter pylori Oncoprotein CagA in Gastric Carcinogenesis. In: Backert, S. (eds) Helicobacter pylori and Gastric Cancer. Current Topics in Microbiology and Immunology, vol 444. Springer, Cham. https://doi.org/10.1007/978-3-031-47331-9_9
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