Molecular anatomy and pathogenic actions of Helicobacter pylori CagA that underpin gastric carcinogenesis
Year: 2019
Type: review
Abstract: Chronic infection with Helicobacter pylori cagA-positive strains is the strongest risk factor for gastric cancer. The cagA gene product, CagA, is delivered into gastric epithelial cells via the bacterial type IV secretion system. Delivered CagA then undergoes tyrosine phosphorylation at the Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs in its C-terminal region and acts as an oncogenic scaffold protein that physically interacts with multiple host signaling proteins in both tyrosine phosphorylation-dependent and -independent manners. Analysis of CagA using in vitro cultured gastric epithelial cells has indicated that the nonphysiological scaffolding actions of CagA cell-autonomously promote the malignant transformation of the cells by endowing the cells with multiple phenotypic cancer hallmarks: sustained proliferation, evasion of growth suppressors, invasiveness, resistance to cell death, and genomic instability. Transgenic expression of CagA in mice leads to in vivo oncogenic action of CagA without any overt inflammation. The in vivo oncogenic activity of CagA is further potentiated in the presence of chronic inflammation. Since Helicobacter pylori infection triggers a proinflammatory response in host cells, a feedforward stimulation loop that augments the oncogenic actions of CagA and inflammation is created in CagA-injected gastric mucosa. Given that Helicobacter pylori is no longer colonized in established gastric cancer lesions, the multistep nature of gastric cancer development should include a "hit-and-run" process of CagA action. Thus, acquisition of genetic and epigenetic alterations that compensate for CagA-directed cancer hallmarks may be required for completion of the "hit-and-run" process of gastric carcinogenesis.
Authors: Atsushi Takahashi-Kanemitsu, Christopher T. Knight, Masanori Hatakeyama
Institution: The University of Tokyo
Language: English
Subfield: Gastroenterology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,390
Awards: G109173334, G1552993075, G1598354214, G1879030589, G2521286739, G3582000651, Understanding of the mechanism of gastric carcinogenesis by the development of the system that visualizes dynamics of the planar cell polarity within gastric epithelial organoids, Mechanism and regulation of gastric carcinogenesis directed by the Helicobacter pylori CagA oncoprotein, Mechanism of Hit-and-Run oncogenesis by the Helicobacter pylori CagA oncoprotein, G5878258037, Elucidating the mechanism of Hit-and-Run carcinogenesis by H. pylori CagA through a CagA-inducible mice model, G6718509927, Investigation of the Roles of Dephosphorylated Parafibromin by SHP2 in Oncogenesis, Investigation of the medical/biological roles of the parafibromin functions regulated by SHP2 oncoprotein, Comprehensive understanding of intracellular signaling pathways deregulated by CagA, the oncogenic scaffold protein from H. pylori, G7753386669, G7879866177, G8511197438, G9000360886
OpenAlex ID: W2992210240