Helicobacter pylori
infection and alcohol intake are independent risk factors in gastric
carcinogenesis; however, until now, the combined effect of H. pylori
infection and alcohol consumption and the specific mechanism is still problematic. Here, we developed a series of mouse models that progress from chronic
gastritis to
gastric cancer, induced by infecting H. pylori combined with chronic alcohol consumption and then determining the molecular mechanism of the progression by flow cytometry, western blotting, qPCR, Mito Traker assay in the
gastric cancer and T-cell lines.
Interleukin-10 (IL-10) knockout mice was used to determine whether
IL-10 deficiency directly contributes to H. pylori and alcohol induced gastric
tumorigenesis. Alcohol consumption, together with H. pylori
infection, causes
gastric cancer;
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 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-1β. IL-1β promotes H. pylori
infection and reduces NKX6.3 gene expression, resulting in increased
cancer cell survival and proliferation.
Gastric cancer can be induced by the combination of H. pylori
infection and chronic alcohol consumption through
IL-10 inhibition induced CD8+ cells dysfunction and NKX6.3 suppression.