Abstract
Background Alcohol is class 1 carcinogen and results in 3.3 million deaths every year. H. pylori is also an important factor for gastric carcinogen. Alcohol consumption is emerging as an important contributor to gastric cancer, but there is no direct or experimental evidence of alcohol and H. pylori infection produce gastric cancer in human and animal model alone. Here, we provide insight into the molecular mechanisms driving gastric carcinogenesis. Results Alcohol consumption, together with H. pylori infection, causes gastric cancer; interleukin-10 (IL-10) downregulation and mitochondrial metabolic dysfunction in CD8+ cells are also involved. IL-10 knockout accelerates tumor development in mice with either H. pylori infection or alcohol induced gastric cancer or both. IL-10 downregulation and CD-8+ cell dysfunction stimulates IL-1β secretion. Specifically, we show IL-10 inhibits glucose uptake and glycolysis and promotes oxidative phosphorylation with lactate inhibition. Consequently, In the absence of IL-10 signaling, CD8+ cells accumulate damaged mitochondria in a mouse model of gastric cancer induced with the combination of alcohol plus H. pylori infection, and this results in mitochondrial dysfunction and production of IL-1 β. IL-1β promotes H. pylori infection and reduces NKX6.3 gene expression, resulting in increased cancer cell survival and proliferation. Conclusions Overall, the molecular mechanisms of gastric carcinogenesis include IL-10 inhibition resulting in lowered host immunity via mitochondrial dysfunction of CD8+ lymphocytes; gastric inflammation due to H. pylori infection, alcohol intake, and IL-1β production; and disruption of gastric-specific tumor suppressor NKX6.3 expression, which increases cancer cell survival and proliferation.
Autophagy-mediated HMGB1 release promotes gastric cancer cell survival via RAGE activation of extracellular signal-regulated kinases 1/2
