Nrf2 Downregulation Contributes to Epithelial-to-Mesenchymal Transition in Helicobacter pylori-Infected Cells.

Abstract

Simple SummaryGastric cancer is mainly linked to Helicobacter pylori infection. It is therefore important to decipher the mechanisms involved in H. pylori-induced gastric carcinogenesis, and especially the early events. We have previously demonstrated that the infection leads to an epithelial-to-mesenchymal transition (EMT) favoring gastric carcinogenesis. H. pylori infection is also associated with high levels of oxidative stress. In this work, we aimed at investigating the modulation of Nrf2, a major regulator of cellular antioxidant response to oxidative stress, upon infection with H. pylori and to decipher its implication in EMT. We demonstrated that H. pylori-induced Nrf2 downregulation may participate in gastric cells’ EMT, one crucial tumorigenic event in gastric cancer. These results could pave the way for new therapeutic strategies using Nrf2 modulators to reduce gastric carcinogenesis associated with H. pylori infection.Background: Gastric cancer, the fifth most common cancer worldwide, is mainly linked to Helicobacter pylori infection. H. pylori induces chronic inflammation of the gastric mucosa associated with high oxidative stress. Our study aimed at assessing the implication of Nrf2, a major regulator of cellular redox homeostasis, in H. pylori-induced gastric carcinogenesis. Methods: Using three different gastric epithelial cell lines, a non-cancerous (HFE-145) and two different subtypes of gastric cancer (AGS and MKN74), we analyzed the modulation of Nrf2 expression over time. After invalidation of Nrf2 by CRISPR-cas9, we assessed its role in H. pylori-induced epithelial-to-mesenchymal transition (EMT). Finally, we evaluated the expression of Nrf2 and ZEB1, a central EMT transcription factor, in human gastric tissues. Results: We first demonstrated that the Nrf2 signaling pathway is differentially regulated depending on the infection stage. Rapidly and transiently activated, Nrf2 was downregulated 24 h post-infection in a VacA-dependent manner. We then demonstrated that Nrf2 invalidation leads to increased EMT, which is even exacerbated after H. pylori infection. Finally, Nrf2 expression tended to decrease in human patients’ gastric mucosa infected with H. pylori. Conclusions: Our work supports the hypothesis that Nrf2 downregulation upon H. pylori infection participates in EMT, one of the most important events in gastric carcinogenesis.