Helicobacter pylori virulence factor CagA promotes tumorigenesis of gastric cancer via multiple signaling pathways

Abstract

Helicobacter pylori (H. pylori) infection is strongly associated with the development of gastric diseases but also with several extragastric diseases. The clinical outcomes caused by H. pylori infection are considered to be associated with a complex combination of host susceptibility, environmental factors and bacterial isolates. Infections involving H. pylori strains that possess the virulence factor CagA have a worse clinical outcome than those involving CagA-negative strains. It is remarkable that CagA-positive H. pylori increase the risk for gastric cancer over the risk associated with H. pylori infection alone. CagA behaves as a bacterial oncoprotein playing a key role in H. pylori-induced gastric cancer. Activation of oncogenic signaling pathways and inactivation of tumor suppressor pathways are two crucial events in the development of gastric cancer. CagA shows the ability to affect the expression or function of vital protein in oncogenic or tumor suppressor signaling pathways via several molecular mechanisms, such as direct binding or interaction, phosphorylation of vital signaling proteins and methylation of tumor suppressor genes. As a result, CagA continuously dysregulates of these signaling pathways and promotes tumorigenesis. Recent research has enriched our understanding of how CagA effects on these signaling pathways. This review summarizes the results of the most relevant studies, discusses the complex molecular mechanism involved and attempts to delineate the entire signaling pathway.

Fig. 1

CagA mediates dysregulation of the Wnt/β-catenin signaling pathway. a. CagA competitively combines with E-cadherin and disrupts the E-cadherin/β-catenin complex formation, causing cytoplasmic and nuclear accumulation of β-catenin. b. H. pylori induces rapid phosphorylation and activation of LRP6. c. CagA induces GSK-3β inactivation via the PI3K/Akt signaling pathway. d. CagA binds GSK-3β directly and depletes GSK-3β activity, inhibiting the phosphorylation and proteasomal degradation of cytosolic β-catenin

Fig. 2

The role of CagA in p53 regulation. a. CagA phosphorylation and activation of HDM2 is mediated by Akt or ERK activation. b. CagA plays a crucial role in p53 shifting to inhibitory p53 isoforms. c. CagA-induced hypermethylation of the p14ARF promoter results in a decrease in p14ARF protein levels that is not sufficient to sequester HDM2 in the nucleus. d. CagA interacts with ASPP2 to recruit and bind p53, which is then degraded by the proteasome. e. CagA induces aberrant expression of AID via NF-κB and thereby elicits a high mutation frequency in p53