[Oncogenic mechanism of Helicobacter pylori].
On a global scale, gastric carcinoma is the second leading course of the cancer-related deaths. Recent studies have provided evidence that cagA-positive Helicobacter pylori plays a causal role for the development of gastric carcinoma. The cagA-encoded CagA protein is delivered into H. pylori-attached gastric epithelial cells via the bacterial type IV secretion system (TFSS). Delivered CagA undergoes tyrosine phosphorylation by Src family kinases at the conserved EPIYA motifs and then specifically binds and deregulates SHP-2 tyrosine phosphatase, a bona fide oncoprotein involved in human malignancies. As a result, CagA causes aberrant mitogenic signal as well as elevated cell motility in gastric epithelial cells. Also, CagA specifically interacts with and inhibits PAR1b/MARK2 polarity-regulating kinase to disrupt tight junctions and cause loss of epithelial apical-basolateral cell polarity. These CagA activities have been suspected to play an important role in gastric carcinogenesis. Indeed, recently generated cagA-transgenic mice expressing CagA systemically developed gastrointestinal carcinomas as well hematopoietic malignancies such as myeloid leukemia and B-cell lymphoma. The observations collectively indicate that H. pylori CagA is the first identified bacterial oncoprotein involved in gastric carcinogenesis.
Hatakeyama
Masanori
M
Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University, Japan.
D000818:Animals; D000942:Antigens, Bacterial / Q000032:analysis*; D001426:Bacterial Proteins / Q000032:analysis*; D016480:Helicobacter pylori / Q000472:pathogenicity*; D051379:Mice; D015513:Oncogene Proteins / Q000032:analysis*; D013274:Stomach Neoplasms / Q000209:etiology*
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D015513:Oncogene Proteins; C080866:cagA protein, Helicobacter pylori