Helicobacter pylori-induced inflammation and epigenetic changes during gastric carcinogenesis

Abstract

The sequence of events associated with the development of gastric cancer has been described as "the gastric precancerous cascade". This cascade is a dynamic process that includes lesions, such as atrophic gastritis, intestinal metaplasia and dysplasia. According to this model, Helicobacter pylori (H. pylori) infection targets the normal gastric mucosa causing non-atrophic gastritis, an initiating lesion that can be cured by clearing H. pylori with antibiotics or that may then linger in the case of chronic infection and progress to atrophic gastritis. The presence of virulence factors in the infecting H. pylori drives the carcinogenesis process. Independent epidemiological and animal studies have confirmed the sequential progression of these precancerous lesions. Particularly long-term follow-up studies estimated a risk of 0.1% for atrophic gastritis/intestinal metaplasia and 6% in case of dysplasia for the long-term development of gastric cancer. With this in mind, a better understanding of the genetic and epigenetic changes associated with progression of the cascade is critical in determining the risk of gastric cancer associated with H. pylori infection. In this review, we will summarize some of the most relevant mechanisms and focus predominantly but not exclusively on the discussion of gene promoter methylation and miRNAs in this context.

Keywords: Epigenetics; Gastric cancer; Helicobacter pylori; Methylation; MicroRNA.

Figure 1

Helicobacter pylori-linked inflammation promotes methylation of genes associated with tumor suppression. A: Helicobacter pylori (H. pylori) induces, via injection of the virulence factors CagA and peptidoglycan (PGN), NF-κB activation, promoting a pro-inflammatory response that increases the expression of cytokines (IL-1β, IL-8) and inducible nitric oxide synthase (iNOS). The latter generates nitric oxide (NO) a mediator of inflammation. Furthermore, the H. pylori-linked activation of NF-κB promotes miR-155 expression, a microRNA associated with gastric pathologies; B: In addition to the direct effects of H. pylori on gastric epithelial cells, the infection activates macrophages, which increase NO production and NO levels in gastric epithelial cells. NO can activate DNA methyltransferase 1 (host DNMT1) to promote DNA methylation in several gene promoter regions; C: Also H. pylori DNA Methyltransferases (Hp DNMTs) may directly promote host DNA methylation in the promoter regions of several genes thought to function as tumor suppressors in gastric cancer. Moreover, infection is associated with promoter methylation and decreased expression of miR210, a miRNA which targets mRNAs implicated in stem cell survival, stalling of the DNA repair system, induction of angiogenesis and cellular differentiation, among others.