Abstract
Injection of the Helicobacter pylori cytotoxin-associated gene A (CagA) is closely associated with the development of chronic gastritis and gastric cancer. Individuals infected with H. pylori possessing the CagA protein produce more reactive oxygen species (ROS) and show an increased risk of developing gastric cancer. Sirtuins (SIRTs) are nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases and mitochondrial SIRT3 is known to be a tumor suppressor via its ability to suppress ROS and hypoxia inducible factor 1α (HIF-1α). However, it is unclear whether increased ROS production by H. pylori is regulated by SIRT3 followed by HIF-1α regulation and whether intracellular CagA acts as a regulator thereof. In this study, we investigated correlations among SIRT3, ROS, and HIF-1α in H. pylori-infected gastric epithelial cells. We observed that SIRT3-deficient AGS cells induce HIF-1α protein stabilization and augmented transcriptional activity under hypoxic conditions. In CagA+ H. pylori infected cells, CagA protein localized to mitochondria where it subsequently suppressed SIRT3 proteins. CagA+ H. pylori infection also increased HIF-1α activity through the ROS production induced by the downregulated SIRT3 activity, which is similar to the hypoxic condition in gastric epithelial cells. In contrast, overexpression of SIRT3 inhibited the HIF-1α protein stabilization and attenuated the increase in HIF-1α transcriptional activity under hypoxic conditions. Moreover, CagA+ H. pylori attenuated HIF-1α stability and decreased transcriptional activity in SIRT3-overexpressing gastric epithelial cells. Taken together, these findings provide valuable insights into the potential role of SIRT3 in CagA+ H. pylori-mediated gastric carcinogenesis and a possible target for cancer prevention via inhibition of HIF-1α.
Highlights
Previous studies have demonstrated that hypoxia is an important microenvironmental factor in promoting tumor progression [1]
H. pylori cytotoxin-associated gene A (CagA) attenuated HIF1α stability and its transcriptional activity in SIRT3overexpressing gastric epithelial cells. These findings suggest that H. pylori CagA induces hypoxia inducible factor 1α (HIF-1α) activity by downregulating SIRT3, followed by increases in reactive oxygen species (ROS) production, which provides a novel mechanism to explain the pathogenesis of H. pylori-mediated gastric carcinogenesis
We knocked down SIRT3 in the gastric epithelial cells with short-hairpinRNA and explored whether SIRT3 knockdown affected the hypoxic activation of HIF-1α
Summary
Previous studies have demonstrated that hypoxia is an important microenvironmental factor in promoting tumor progression [1]. Epidemiological studies have suggested that the development of gastric cancer may be attributed to hypoxia-induced reactive oxygen species (ROS) [2] and that ROS generated within the gastric mucosa are related to continuous exposure to H. pylori infection, ingested food, and cigarette smoking, etc. Suzuki et al found that ROS production in gastric epithelial cells was significantly enhanced by infection with CagA-positive H. pylori strains, resulting in an extensive accumulation of neutrophils [5], and was involved in tumor initiation, enhanced expression of oncogenes, and increased cell proliferation. Mitochondrial electron transport chain-generated ROS can stabilize HIF-1α, resulting in the transcription of genes involved in glucose transport and glycolytic enzymes, as well as promoting cell proliferation [8, 9]
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