Oxidative Stress Resulting From Helicobacter pylori Infection Contributes to Gastric Carcinogenesis

Abstract

Helicobacter pylori is a gram-negative, microaerophilic bacterium that infects the stomach and can lead to, among other disorders, the development of gastric cancer. The inability of the host to clear the infection results in a chronic inflammatory state with continued oxidative stress within the tissue. Reactive oxygen species and reactive nitrogen species produced by the immune and epithelial cells damage the host cells and can result in DNA damage. H pylori has evolved to evoke this damaging response while blunting the host's efforts to kill the bacteria. This long-lasting state with inflammation and oxidative stress can result in gastric carcinogenesis. Continued efforts to better understand the bacterium and the host response will serve to prevent or provide improved early diagnosis and treatment of gastric cancer.

Keywords: AP Endonuclease; APE1, apurinic/apyrimidinic endonuclease 1; BabA, blood group antigen binding adhesion; CagA, cytotoxin-associated gene A; DNA Damage; Gastric Cancer; H pylori; IL, interleukin; NADPH, nicotinamide adenine dinucleotide phosphate; NapA, neutrophil activating factor A; Nox, nicotinamide adenine dinucleotide phosphate oxidase; O2-, superoxide; OH, hydroxyl radical; Oxidative Stress; RNS, reactive nitrogen species; ROS, reactive oxygen species; TGF-β, transforming growth factor β; VacA, vacuolating cytotoxin A; iNOS, inducible nitric oxide synthase.

Figure 1

Oxidative stress may result in DNA damage. ROS produced during H pylori infection can cause DNA damage. The oxidation of the DNA often occurs on deoxyguanosine, resulting in 8-hydroxy-2′deoxyguanosine (8-OHdG). This base then can be lost as a result of the damage, causing an abasic site. This abasic site produces a single-strand break in the DNA if not repaired. Double-strand breaks can develop from single-strand breaks or from other sources such as chemicals or collapsed replication forks. Both single- and double-strand breaks can increase chromosomal instability and lead to errors during replication that may increase the chances of a tumor formation.

Figure 2

H pylori infection leads to oxidative stress.H pylori infection results in ROS production by the immune and epithelial cells in an attempt to kill the bacteria. Virulence factors from H pylori such as CagA are injected into the epithelial cell while VacA is secreted from the bacteria and trapped in an intracellular vesicle. The virulence factors trigger multiple cellular responses including the production of intrinsic ROS. The ROS result in DNA damage in the epithelial cells, activating APE1, which then translocates to the nucleus to regulate gene transcription and to attempt to repair the DNA. Spermine oxidase (SMO) also is activated and results in DNA damage, as well as acting on the mitochondria membrane. Immune cells recruited to the area by virulence factors including NapA release extrinsic ROS in an attempt to clear the infection, resulting in more damage to the area.