Influence of Helicobacter pylori oncoprotein CagA in gastric cancer: A critical-reflective analysis

Abstract

Gastric cancer is the fifth most common malignancy and third leading cancer-related cause of death worldwide. Helicobacter pylori is a Gram-negative bacterium that inhabits the gastric environment of 60.3% of the world's population and represents the main risk factor for the onset of gastric neoplasms. CagA is the most important virulence factor in H. pylori, and is a translocated oncoprotein that induces morphofunctional modifications in gastric epithelial cells and a chronic inflammatory response that increases the risk of developing precancerous lesions. Upon translocation and tyrosine phosphorylation, CagA moves to the cell membrane and acts as a pathological scaffold protein that simultaneously interacts with multiple intracellular signaling pathways, thereby disrupting cell proliferation, differentiation and apoptosis. All these alterations in cell biology increase the risk of damaged cells acquiring pro-oncogenic genetic changes. In this sense, once gastric cancer sets in, its perpetuation is independent of the presence of the oncoprotein, characterizing a "hit-and-run" carcinogenic mechanism. Therefore, this review aims to describe H. pylori- and CagA-related oncogenic mechanisms, to update readers and discuss the novelties and perspectives in this field.

Keywords: CagA; EPIYA motifs; Gastric cancer; Helicobacter pylori; Hit-and-run carcinogenesis; Virulence factors.

Figure 1

Helicobacter pylori oncoprotein: molecular structure and CagA-mediated carcinogenesis underlying mechanisms. A: Structural domain differences between East Asian and western CagA. CagA tertiary structure is characterized by a structured N-terminal region and an unstructured C-terminal tail. The oncoprotein contains repetitive sequences in its C-terminal polymorphic region, known as the EPIYA motifs and CM motif. EPIYA-A and EPIYA-B motifs were identified in almost all CagA-positive H. pylori strains, followed by one, two, or three EPIYA-C sequences in western strains, or an EPIYA-D segment in East Asian strains. The CM motif, although highly conserved, possesses a 5-amino-acid difference between East Asian and western strains, hence distinguishing East Asian and Western CagA; B: Molecular mechanisms of CagA-mediated carcinogenesis. Upon translocation, CagA EPIYA motifs are tyrosine-phosphorylated by Src family or c-Abl kinases of the host cell. After phosphorylation, CagA localizes to the inner leaflet of the plasmatic membrane and acts as a promiscuous scaffold or hub protein that simultaneously disturbs multiple host signaling pathways, involved in regulation of a large range of cellular processes, including proliferation, differentiation and apoptosis. Ultimately, the disharmonic interaction between CagA and host proteins leads to pro-oncogenic cellular alterations. CM: CagA-multimerization; CM^W: western CagA.

Figure 2

Simplified model of CagA-mediated hit-and-run carcinogenesis. The pro-oncogenic properties of CagA are already well established. However, genetic and epigenetic alterations caused by this oncoprotein provide a favorable environment for carcinogenesis, independently of its presence, in a hit-and-run carcinogenesis mechanism. In this sense, through interaction with various host proteins, CagA leads to chromosomal instability, double-strand breaks and repeated nucleotide mutations, which are correlated to gastric cancer development. CM^W: western CagA.

Figure 3

Status of the current understanding regarding CagA-related pathogenic mechanisms. EMT: Epithelial to mesenchymal transition; CEACAMs: Carcinoembryonic antigen-related cell adhesion molecules; Grb2: Growth factor receptor-bound protein 2; ASPP2: Apoptosis-stimulating protein of p53 2; SHP2: Domain-containing protein tyrosine phosphatase 2; SHIP2: Src homology 2 domain-containing inositol 5'-phosphatase 2; RUNX3: Runt-related transcription factor 3; PAR1: Partitioning-defective 1; NikS: Nickel-regulated sRNA.