Research Papers:

Demonstration of potential link between Helicobacter pylori related promoter CpG island methylation and telomere shortening in human gastric mucosa

Tomomitsu Tahara _, Tomoyuki Shibata, Masaaki Okubo, Tomohiko Kawamura, Noriyuki Horiguchi, Takamitsu Ishizuka, Naoko Nakano, Mitsuo Nagasaka, Yoshihito Nakagawa and Naoki Ohmiya

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Oncotarget. 2016; 7:43989-43996. https://doi.org/10.18632/oncotarget.9764

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Tomomitsu Tahara1, Tomoyuki Shibata1, Masaaki Okubo1, Tomohiko Kawamura1, Noriyuki Horiguchi1, Takamitsu Ishizuka1, Naoko Nakano1, Mitsuo Nagasaka1, Yoshihito Nakagawa1, Naoki Ohmiya1

1Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan

Correspondence to:

Tomomitsu Tahara, email: tomomiccyu@yahoo.co.jp

Keywords: DNA methylation, telomere length, gastric mucosa, H. pylori, gastritis

Received: October 24, 2015    Accepted: May 02, 2016    Published: June 01, 2016


Background: Telomere length shortening in Helicobacter pylori (H. pylori) infected gastric mucosa constitutes the earliest steps toward neoplastic transformation. In addition to this genotoxic changes, epigenetic changes such as promoter CpG island (PCGI) methylation are frequently occurred in H. pylori infected gastric mucosa. The aim of this study was to investigate a potential link between H. pylori related PCGI methylation and telomere length shortening in the human gastric mucosa.

Methods: Telomere length was measured in non-neoplastic gastric mucosa from 106 cancer-free subjects. To identify H. pylori related PCGI methylation, bisulfite pyrosequencing was used to quantify the methylation of 49 PCGIs from 47 genes and LINE1 repetitive element

Results: We identified five PCGIs (IGF2, SLC16A12, SOX11, P2RX7 and MYOD1), which the methylation is closely associated with H. pylori infection. Hypermethylation of all these PCGIs was associated with development of pathological state from normal to mild, active, and atrophic gastritis (P<0.001) and lower pepsinogen I/II ratio (P<0.05), an indicator for gastric mucosal atrophy. Telomere shortening was significantly associated with mean Z score methylation of five PCGIs (R=-0.39, P<0.0001) and four of these locus (IGF2: R=-0.35, P=0.0003, SLC16A12: R=-0.35, P=0.0002, P2RX7: R=-0.29, P=0.003, and MYOD1: R=-0.33, P=0.0005). Multivariate analysis revealed that telomere shortening held an increased risk for hypermethylation (odds ratio: 1.71, 95% confidence interval: 1.11-2.63, P=0.016).

Conclusion: Potential link between H. pylori related PCGI methylation and telomere shortening emphasize the importance of genotoxic-epigenetic interaction in the pathological state of H. pylori infected gastric mucosa.

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