TY - JOUR
T1 - Gastric tumorigenesis induced by combining Helicobacter pylori infection and chronic alcohol through IL-10 inhibition
AU - Aziz, Faisal
AU - Chakraborty, Abhijit
AU - Liu, Kangdong
AU - Zhang, Tianshun
AU - Li, Xiang
AU - Du, Ruijuan
AU - Monts, Josh
AU - Xu, Gang
AU - Li, Yonghan
AU - Bai, Ruihua
AU - Dong, Zigang
N1 - Funding Information:
The project was supported by the National Natural Science Foundation of China (NSFC) research grant numbers 81750110551 and 82073075.
Publisher Copyright:
© 2021 The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
PY - 2022/2/1
Y1 - 2022/2/1
N2 - 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.
AB - 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.
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U2 - 10.1093/carcin/bgab114
DO - 10.1093/carcin/bgab114
M3 - Article
C2 - 34919670
AN - SCOPUS:85127834275
VL - 43
SP - 126
EP - 139
JO - Carcinogenesis
JF - Carcinogenesis
SN - 0143-3334
IS - 2
ER -