Research Advances on the Role of Helicobacter pylori CagA Protein in the Pathogenesis of Gastric Cancer

Abstract

Helicobacter pylori (Hp) infection is a key environmental factor in the development of gastric cancer, with its virulence factor, the cytotoxin-associated gene A (CagA) protein, playing a central role in the pathogenic process. Extensive research data indicate that in regions with a high incidence of gastric cancer, the infection rate of Hp is significantly higher than in low-incidence areas, and Hp infection shows a clear geographical correlation with the incidence of gastric cancer. Moreover, the occurrence of intestinal metaplasia in Hp-positive patients is far more frequent than in Hp-negative individuals, suggesting that Hp may promote the formation of intestinal metaplasia.

This article systematically reviews recent research advances on the mechanisms by which the CagA protein drives the development and progression of gastric cancer, including interference with host cell signaling pathways, induction of epithelial-mesenchymal transition (EMT), promotion of immune evasion, synergy with environmental carcinogens, and regulation of key metabolic enzymes. As a major virulence factor of H. pylori, CagA can activate signaling networks such as SHP2, PI3K/Akt, MAPK, and Wnt/β-catenin through both phosphorylation-dependent and independent pathways. Current evidence suggests that this disrupts the balance between cell proliferation and apoptosis, although its role in pro-apoptotic effects may be relatively limited.

The aberrant activation of these signaling pathways may ultimately lead to uncontrolled cell proliferation, inhibited apoptosis, genomic instability, and microenvironment remodeling. In-depth investigation of the carcinogenic mechanisms of CagA can provide an important theoretical basis for molecular typing, risk prediction, and targeted intervention of gastric cancer, holding profound significance for its prevention and treatment.