The role of Helicobacter pylori CagA oncoprotein in neoplastic transformation of gastric epithelial cells

Chronic infection with Helicobacter pylori, especially cagA-positive strains, plays an etiological role in the development of gastric cancer. The Cytotoxin-associated gene A (CagA) protein, encoded by cagA, is delivered into gastric epithelial cells via bacterial type IV secretion, where it undergoes tyrosine phosphorylation at the Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs. Host cell-delivered CagA then acts as a nonphysiological scaffold/hub by interacting with multiple signaling molecules, most notably the pro-oncogenic phosphatase SHP2 and the polarity-regulating kinase PAR1b, in both tyrosine phosphorylation-dependent and -independent manners. CagA-mediated manipulation of intracellular signaling promotes neoplastic transformation of gastric epithelial cells. Indeed, transgenic expression of CagA in experimental animals has confirmed the oncogenic potential of the bacterial protein. Structural polymorphism of CagA influences its scaffold function, which may underlie the geographic difference in the incidence of gastric cancer. Meanwhile, since CagA is no longer required for the maintenance of established gastric cancer, CagA appears to promote gastric carcinogenesis through a hit-and-run mechanism. In this chapter, these facets of CagA and their impact on gastric carcinogenesis will be discussed in detail.