Helicobacter pylori-Mediated Immunity and Signaling Transduction in Gastric Cancer.

Nozomi Ito,Qian Xie,Hideki Ueno,Nariyoshi Shinomiya,Hironori Tsujimoto

doi:10.3390/jcm9113699

Abstract

Helicobacter pylori infection is a leading cause of gastric cancer, which is the second-most common cancer-related death in the world. The chronic inflammatory environment in the gastric mucosal epithelia during H. pylori infection stimulates intracellular signaling pathways, namely inflammatory signals, which may lead to the promotion and progression of cancer cells. We herein report two important signal transduction pathways, the LPS-TLR4 and CagA-MET pathways. Upon H. pylori stimulation, lipopolysaccharide (LPS) binds to toll-like receptor 4 (TLR4) mainly on macrophages and gastric epithelial cells. This induces an inflammatory response in the gastric epithelia to upregulate transcription factors, such as NF-κB, AP-1, and IRFs, all of which contribute to the initiation and progression of gastric cancer cells. Compared with other bacterial LPSs, H. pylori LPS has a unique function of inhibiting the mononuclear cell (MNC)-based production of IL-12 and IFN-γ. While this mechanism reduces the degree of inflammatory reaction of immune cells, it also promotes the survival of gastric cancer cells. The HGF/SF-MET signaling plays a major role in promoting cellular proliferation, motility, migration, survival, and angiogenesis, all of which are essential factors for cancer progression. H. pylori infection may facilitate MET downstream signaling in gastric cancer cells through its CagA protein via phosphorylation-dependent and/or phosphorylation-independent pathways. Other signaling pathways involved in H. pylori infection include EGFR, FAK, and Wnt/β-Catenin. These pathways function in the inflammatory process of gastric epithelial mucosa, as well as the progression of gastric cancer cells. Thus, H. pylori infection-mediated chronic inflammation plays an important role in the development and progression of gastric cancer.

Highlights

Helicobacter pylori is a microaerophilic bacterium that infects the gastric mucosal epithelium through colonization and triggers chronic inflammation [1]
A conserved motif in the C-terminal region of Cytotoxin-associated gene A (CagA) known as the conserved repeat responsible for phosphorylation-independent activity (CRPIA) motif may interact with activated MET, leading to the activation of PI3K/Akt signaling for the proliferation of gastric cancer cells after H. pylori infection, which in turn contributes to the H. pylori-associated chronic gastric proliferative reaction and NF-kB signaling associated with the pro-inflammatory responses [48]
H. pylori infection-associated chronic inflammation is an important factor in the development and subsequent progression of gastric cancer

Summary

Introduction

Helicobacter pylori is a microaerophilic bacterium that infects the gastric mucosal epithelium through colonization and triggers chronic inflammation [1]. H. pylori infection-mediated chronic inflammation plays an important role in the development and progression of gastric cancer. We report the nature of H. pylori-induced inflammation and discuss the importance of bacterial-epithelial cell interaction in gastric cancer progression with a focus on the signal transduction pathways involved in gastric epithelial cells as well as inflammatory mediator cells, the LPS-TLR4 and CagA-MET pathways.

Results

Conclusion