| [ Summary ] |
Gastric carcinoma, a major malignancy arising from the upper gastrointestinal tract, is in most cases caused by chronic infection with Helicobacter pylori. Recent studies have revealed that H. pylori-derived virulence factor CagA plays a pivotal role in the development ofH. pylori-mediated gastric cancer. CagA is delivered into gastric epithelial cells via the bacterial type IV secretion system, where it undergoes tyrosine phosphorylation by Src and Abl kinases. Tyrosine phosphorylated CagA then acquires the ability to interact with and deregulate SHP-2 phosphatase, a bonafide oncoprotein involved in a variety of human malignancies. CagA also binds to and inhibits PAR1b / MARK2 polarity-regulating kinase to disrupt tight junctions and epithelial apical-basolateral polarity. These CagA activities may collectively contribute to the transformation of gastric epithelial cells. Indeed, transgenic expression of CagA in mice results in the development of gastrointestinal and hematological malignancies, indicating that CagA is the first bacterial oncoprotein acting in mammalian cells. The oncogenic potential of CagA may be potentiated by the presence of chronic inflammation, which aberrantly induces activation-induced cytidine deaminase (AID), a member of the DNA / RNA editing enzyme family. Ectopically expressed AID may contribute to gastric carcinogenesis by increasing the chances that epitbelial cells introduce mutations into cancer-related genes such as P 53. |