Rectifying the Epigenetic Field Defect in Gastric Carcinogenesis

Gastric cancer is undoubtedly a fatal malignancy worldwide with high incidence and dismal prognosis. Its formation and development can be driven by genetic defects, dietary factors, alcohol consumption, viral infection, etc. Despite the multifactorial nature, more than 80% of gastric cancers are closely related to Helicobacter pylori (H. pylori) infection [1]. It is believed that H. pylori triggers chronic gastritis that results in gastric atrophy, intestinal metaplasia and dysplasia, and then finally to adenocarcinoma. Such microbial infection is associated with strong host response such as cytokine stimulation and neutrophil activation which play an important driver role in gastric carcinogenesis. The stimulated cytokines include pro-inflammatory interleukin-1β (IL-1β), IL-2, IL-6, IL-8 and tumor necrosis factor alpha (TNF-α), of which the IL-8 action in stimulating neutrophils is significantly enhanced upon infection by CagA-positive H. pylori [2]. In addition to immune system, H. pylori is known to perturb the expression of host genes by different mechanisms. For examples, H. pylori can cause promoter hypermethylation and silencing of FOXD3, leading to decreased levels of cell death modulators CYFIP2 and RARB to favor the proliferation of gastric cancer cells [3]. Moreover, H. pylori can epigenetically down-regulate the transcription of miR490-3p, thereby resume the expression of its direct target SMARCD1 which is a member of the SWItch/SucroseNonFermentable (SWI/ SNF) chromatin remodeling family with oncogenic functional roles [4]. The H. Pylori deregulated host genes are of clinical significance as demonstrated by their respective correlations with various clinicpathological features of gastric cancer patients [3,4].