Involvement of tumor necrosis factor-α in the upregulation of CXCR4 expression in gastric cancer induced by Helicobacter pylori

Abstract

BackgroundH. pylori, whose infection increases tumor invasiveness and metastasis, is generally labelled as the strongest risk factor for the development of gastric cancer. It appears not to be a coincidence that there is also an overexpression of CXCR4 and an obvious involvement in gastric cancer metastasis. The aim of this study attempts to investigate and further to establish a link between them. With H. pylori being a potent inducer of TNF-α, whether TNF-α, a tumor promoter, is involved in the induction of CXCR4 expression by H. pylori was also under research in this study.MethodsExpression of CXCR4, TNF-α, IL-6 and IL-1β mRNA was determined by real-time PCR. CXCR4 protein expression was detected by Western blotting. Concentrations of TNF-α, IL-6 and IL-1β in cell culture supernatants were measured using the Quantikine Elisa kit. To abrogate TNF-α expression in HGC27 cells, TNF-α RNAi plasmid was used to transfect them.ResultsLevels of CXCR4 and TNF-α mRNA were significantly higher in H. pylori-positive gastric cancers (n = 19) compared to H. pylori-negative ones (n = 15). A subsequently Spearman's rank correlation test showed there was a positive correlation between the level of CXCR4 mRNA and that of TNF-α in 34 primary gastric cancers. Other results followed: Expression of CXCR4 and TNF-α was upregulated in gastric cancer cell MKN45 and HGC27 after infection with H. pylori 26695 (cag PAI+ ) or Tx30a (cag PAI- ); The induction of CXCR4 expression by H. pylori was inhibited significantly by a neutralizing TNF-α antibody, infliximab; CXCR4 expression was upregulated in MKN45 cells after treatment with exogenous TNF-α or co-culture with macrophage, and was downregulated in HGC27 cells after transfection with TNF-α RNAi plasmid. There was a significant increase in the migration of MKN45 cells treated with H. pylori 26695, and a strong inhibition when AMD 3100, a CXCR4 antagonist, or infliximab, was added.ConclusionsOur findings demonstrated that H. pylori upregulates CXCR4 expression in gastric cancer through TNF-α.

Gastric Cancer: Clinical Aspects, Epidemiology and Molecular Background

“…Finally, H. pylori can induce CXCR4 expression in GC by upregulation of TNF-a which leads to a higher migration rate in epithelial cell lines [65]. These results deliver valuable insights into GC biology that can be used for the development of new therapeutic agents.…”

The role of CXC chemokines in the transition of chronic inflammation to esophageal and gastric cancer

“…H. pylori infection has been reported to increase tumor invasion and metastasis. In this context, H. pylori increased CXCR4 expression in gastric cancer through increased secretion of TNF-α [180]. Besides the expression of CXCR4 by gastric tumor cells, CXCR4 has also been found in leukocytes and microvascular blood vessels, confirming that SDF-1 binds to endothelial cells (Table 2) [174].…”

Influence of functional polymorphisms in TNF-α, IL-8, and IL-10 cytokine genes on mRNA expression levels and risk of gastric cancer

“…Models with TNF-α-deficient mice have revealed that it is one of the essential cytokines for gastric cancer promotion, along with IL-1 and IL-6 [48]. High TNF-α mRNA expression has been reported in gastric cancer cases [49], as well as in gastric lesion cases such as peptic ulcers [50], chronic gastritis, intestinal metaplasia, and dysplasia [51], whether associated with H. pylori infection or not. Thus, these data corroborate our results.…”