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

Core tip: CagA is a translocated effector protein that induces morphofunctional modifications in gastric epithelial cells and persistent chronic gastric inflammation. Upon translocation, the bacterial oncoprotein acts as a promiscuous scaffold or hub protein, which is capable of disrupting multiple host signaling pathways, thereby inducing precancerous cellular alterations. This review aims to describe Helicobacter pylori- and CagA-related oncogenic mechanisms, as well as to discuss the novelties and perspectives in this field.