Gastric tumorigenesis induced by combining Helicobacter pylori infection and chronic alcohol through IL-10 inhibition

Faisal Aziz, Abhijit Chakraborty, Kangdong Liu, Tianshun Zhang, Xiang Li, Ruijuan Du, Josh Monts, Gang Xu, Yonghan Li, Ruihua Bai, Zigang Dong

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)126-139
Number of pages14
JournalCarcinogenesis
Volume43
Issue number2
DOIs
StatePublished - Feb 1 2022

Bibliographical note

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.

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