Hypoxia exacerbates the malignant transformation of gastric epithelial cells induced by long-term
H. pylori
infection
Authors: He Yang , Zhang Xiulin , Zhang Xiaolu , Fu Bo , Xing Jin , Fu Rui , Lv Jianyi , Guo Meng , Huo Xueyun , Liu Xin , Lu Jing , Cao Lixue , Du Xiaoyan , Ge Zhongming , Chen Zhenwen , Lu Xuancheng , Li Changlong 
Published: June 2024

Helicobacter pylori
is a microaerophilic Gram-negative bacterium that resides in the human stomach and is classified as a class I carcinogen for gastric cancer. Numerous studies have demonstrated that
H. pylori
infection plays a role in regulating the function of host cells, thereby contributing to the malignant transformation of these cells. However,
H. pylori
infection is a chronic process, and short-term cellular experiments may not provide a comprehensive understanding of the
in vivo
situation, especially when considering the lower oxygen levels in the human stomach. In this study, we aimed to investigate the mechanisms underlying gastric cell dysfunction after prolonged exposure to
H. pylori
under hypoxic conditions. We conducted a co-culture experiment using the gastric cell line GES-1 and
H. pylori
for 30 generations under intermittent hypoxic conditions. By closely monitoring cell proliferation, migration, invasion, autophagy, and apoptosis, we revealed that sustained
H. pylori
stimulation under hypoxic conditions significantly influences the function of GES-1 cells. This stimulation induces epithelial-mesenchymal transition and contributes to the propensity for malignant transformation of gastric cells. To confirm the
in vitro
results, we conducted an experiment involving Mongolian gerbils infected with
H. pylori
for 85 weeks. All the results strongly suggest that the Nod1 receptor signaling pathway plays a crucial role in
H. pylori
-related apoptosis and autophagy. In summary, continuous stimulation by
H. pylori
affects the functioning of gastric cells through the Nod1 receptor signaling pathway, increasing the likelihood of cell carcinogenesis. The presence of hypoxic conditions further exacerbates this process.

IMPORTANCE

Deciphering the collaborative effects of
Helicobacter pylori
infection on gastric epithelial cell function is key to unraveling the development mechanisms of gastric cancer. Prior research has solely examined the outcomes of short-term
H. pylori
stimulation on gastric epithelial cells under aerobic conditions, neglecting the bacterium’s nature as a microaerophilic organism that leads to cancer following prolonged stomach colonization. This study mimics a more genuine
in vivo
infection scenario by repeatedly exposing gastric epithelial cells to
H. pylori
under hypoxic conditions for up to 30 generations. The results show that chronic exposure to
H. pylori
in hypoxia substantially increases cell migration, invasion, and epithelial-mesenchymal transition, while suppressing autophagy and apoptosis. This highlights the significance of hypoxic conditions in intensifying the carcinogenic impact of
H. pylori
infection. By accurately replicating the
in vivo
gastric environment, this study enhances our comprehension of
H. pylori
’s pathogenic mechanisms in gastric cancer.