Abstract

Infection by Helicobacter pylori (Hp) is the main risk factor associated with the development and progression of precancerous lesions to gastric cancer. Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is activated by endoplasmic reticulum (ER) stress, and ER stress-induced apoptotic cell death has been associated with Hp infection. Survivin, an inhibitor of apoptosis, is downregulated in the mucosa of Hp infected subjects and loss of survivin in gastric cells correlates with reduced viability. Here, we determined whether Hp-induced changes in PERK contribute to the loss of survivin, previously associated with the genesis of gastric cancer precancerous lesions. Our results show that PERK is activated in the early stages of Hp infection in the human gastric mucosa affected by gastritis and PERK activation coincided with reduced survivin levels compared with Hp-negative gastritis. Upon Hp infection in vitro, PERK silencing restored survivin abundance and its activity increased survivin loss, in parallel with a partial downstream activation of the α- subunit of eukaryotic initiation factor-2 (eIF2α). Our results suggest a novel mechanism by which Hp-stimulated PERK reduces gastric cell viability/proliferation by downregulating survivin and is likely to favour the genesis of gastric cancer precancerous lesions.