Activation of Aquaporin 5 by carcinogenic Helicobacter pylori infection promotes epithelial‐mesenchymal transition via the MEK/ERK pathway

Abstract

Background Helicobacter pylori (H. pylori) is a major risk factor for gastric cancer. The water channel protein Aquaporin 5 (AQP5) is involved in the tumorigenesis and progression of various cancers. In this study, we aimed to explore the role of AQP5 in H. pylori‐induced gastric carcinogenesis. Materials and Methods We collected 160 samples which inculded CNAG, IM, Dys and gastric cancer from patients who underwent endoscopy and detected the expression of AQP5. In vivo and vitro H. pylori infection models, we explored the relationship between AQP5 and H. pylori. Plasmid, siRNA and inhibitors were used to investigated the relationship between AQP5 and EMT and the role of AQP5 in H. pylori‐induced gastric carcinogenesis. Result AQP5 expression was gradually increased in human gastric tissues with the progression of chronic nonatrophic gastritis to gastric cancer and associated with the H. pylori infection status. In vivo and in vitro studies showed that H. pylori infection induced AQP5 expression in gastric epithelial cells in a CagA‐dependent manner. Knockdown of AQP5 reversed H. pylori‐induced cell proliferation and invasion, and ‐suppressed cell apoptosis. Additionally, knockdown of AQP5 suppressed H. pylori‐induced Epithelial‐mesenchymal transition (EMT) phenotypes by regulating transcriptional factors, mesenchymal markers, and epithelial markers. Conclusions We explored the underlying mechanism and our results indicated that knockdown of AQP5 significantly suppressed H. pylori infection‐induced phosphorylation of ERK1/2, MEK and the expression levels of downstream genes. Treatment with an ERK inhibitor suppressed the EMT induced by H. pylori infection. Taken together, this study suggest that pathogenic H. pylori infection promotes AQP5 expression to induce the EMT via the MEK/ERK signaling pathway.

Helicobacter pylori infection activates Wnt/β-catenin pathway to promote the occurrence of gastritis by upregulating ASCL1 and AQP5

“…The finding in the present study uncovered that AQP5 was upregulated in gastric mucosa and GECs infected with H. pylori . Similarly, a published work has also revealed that AQP5 expression elevates in GECs in gastritis, which is related with the H. pylori infection [ 9 ]. Moreover, it was found that silencing of AQP5 could restrain levels of inflammatory factor (TNF-α and IL-1β) and apoptosis of GECs in mice with H. pylori -related gastritis.…”

“…It is interesting to note that H. pylori infection could elevate Aquaporin 5 (AQP5) expression in gastric epithelial cells (GECs), which promotes the development of gastritis [ 9 ]. AQP5, a member of AQPs, is essential for regulating water transport in healthy tissues and is related to multiple human cancers, such as gastric cancer [ 10 ].…”

“…As serpentine membrane proteins, aquaporins (AQPs) promote the movement of water across the biological membrane [ 11 ]. Intriguingly, H. pylori infection has been documented to enhance AQP5 levels in gastric epithelial cells, while ablation of AQP5 was found to negate H. pylori- triggered cell invasive and proliferative properties [ 9 ].…”

Aquaporins in Glandular Secretion

“…Lower levels of miR-877 and miR874, shown to regulate AQP3 and AQP5 expression, respectively, may account for the increased AQP3 and AQP5 expression and epithelial mesenchymal transition [114,115]. AQP3 and AQP5 expression has been shown to be positively correlated with gastric mucosal disease progression in gastric carcinoma and other stages of gastric diseases as well as with Helicobacter pylori infection [116,117]. Helicobacter pylori promote AQP3 and AQP5 expression (through the activation of downstream HIF-1α or ERK1/ 2, MEK, respectively) that could be used as novel molecular targets for therapeutic interventions [116,117].…”

“…AQP3 and AQP5 expression has been shown to be positively correlated with gastric mucosal disease progression in gastric carcinoma and other stages of gastric diseases as well as with Helicobacter pylori infection [116,117]. Helicobacter pylori promote AQP3 and AQP5 expression (through the activation of downstream HIF-1α or ERK1/ 2, MEK, respectively) that could be used as novel molecular targets for therapeutic interventions [116,117]. Furthermore, as the expression of certain AQPs is associated with better or poor overall survival of patients with gastric cancer, it can be used as predictive prognostic gastric cancer biomarker [110,118].…”