Mechanisms for the induction of gastric cancer by Helicobacter pylori infection: aberrant DNA methylation pathway

Abstract

Multiple pathogenic mechanisms by whichHelicobacter pylori infection induces gastric cancer have been established in the last two decades. In particular, aberrant DNA methylation is induced in multiple driver genes, which inactivates them. Methylation profiles in gastric cancer are associated with specific subtypes, such as microsatellite instability. Recent comprehensive and integrated analyses showed that many cancer-related pathways are more frequently altered by aberrant DNA methylation than by mutations. Aberrant DNA methylation can even be present in noncancerous gastric mucosae, producing an ''epigenetic field for cancerization.'' Mechanistically, H. pylori-induced chronic inflammation, but not H. pylori itself, plays a direct role in the induction of aberrant DNA methylation. The expression of three inflammation-related genes, Il1b, Nos2, and Tnf, is highly associated with the induction of aberrant DNA methylation. Importantly, the degree of accumulated aberrant DNA methylation is strongly correlated with gastric cancer risk. A recent multicenter prospective cohort study demonstrated the utility of epigenetic cancer risk diagnosis for metachronous gastric cancer. Suppression of aberrant DNA methylation by a demethylating agent was shown to inhibit gastric cancer development in an animal model. Induction of aberrant DNA methylation is the major pathway by which H. pylori infection induces gastric cancer, and this can be utilized for translational opportunities.

Helicobacter pylori infection leads to KLF4 inactivation in gastric cancer through a TET1‐mediated DNA methylation mechanism

“…Tumor incidence is linked to gene regulation and is also affected by environmental factors. H pylori has been defined as the first kind of biological carcinogenic factor in GC . However, KLF4 plays a role as a tumor suppressor gene in GC.…”

“…The most important function of TET1 (ten‐eleven translocation) protease activity is to convert 5‐methylcytosine (5‐mC) into 5‐hydroxymethylcytosine (5‐hmC), while the TET2 and TET3 mRNAs do not differ in GC . Tet1 expression was also significantly reduced in CagA + GC tissues compared with that in noncancerous tissues . According to many studies and experimental data, H pylori infection/CagA promotes the transport of the DNMT1 and DNMT3B proteins (DNA methyltransferase 3 B) into the nucleus of cells, and this may be related to the silencing of transcriptional expression, such as E‐cadherin (CDH1) and forkhead box (Fox) .…”

“…In addition, ten‐eleven translocation (TET) enzymes mainly oxidize 5‐methylcytosine (5‐mC) into 5‐hydroxymethyl cytosine (5‐hmC) and participate in cytosine methylation and cell differentiation . However, it has been reported that TET1 decreased prominently in CagA‐infected GC tissues compared with that in para‐carcinoma tissues . Hence, we sought to explore how KLF4 is inactivated in GC and aimed to analyze the relationships among CagA, KLF4, and TET1.…”

Genetic Alterations in Gastric Cancer Associated with Helicobacter pylori Infection

“…Contrary to the methylation that is generated only in the differentiated cells will disappear when they are replaced with new cells without methylation that are derived from some SC without methylation, of important way this information indicates to us that the methylation induced in the differentiated cells will be a transient component (76). …”

“…The degree of aberrant DNA methylation is correlated with the risk of gastric cancer. It is known that the induction of DNA methylation is the main route by which H. pylori infection induces gastric cancer; this information may be useful to decrease gastric cancer (76). …”