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Original article
CagA mediates epigenetic regulation to attenuate let-7 expression in Helicobacter pylori-related carcinogenesis
  1. Yoshito Hayashi1,
  2. Masahiko Tsujii1,
  3. Jun Wang2,
  4. Jumpei Kondo1,
  5. Tomofumi Akasaka1,
  6. Ying Jin1,
  7. Wei Li1,
  8. Toru Nakamura3,
  9. Tsutomu Nishida1,
  10. Hideki Iijima1,
  11. Shingo Tsuji4,
  12. Sunao Kawano5,
  13. Norio Hayashi6,
  14. Tetsuo Takehara1
  1. 1Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
  2. 2Department of Gastroenterology, No. 451 Hospital, Xi'an, China
  3. 3Department of Clinical Laboratory Science, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
  4. 4Osaka Seamen's Hospital, Osaka, Osaka, Japan
  5. 5Health Care Center, Hankyu Hanshin Business Associate, Nishinomiya, Hyogo, Japan
  6. 6Kansai Rousai Hospital, Amagasaki, Hyogo, Japan
  1. Correspondence to Dr Tetsuo Takehara, Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan; takehara{at}gh.med.osaka-u.ac.jp

Abstract

Objective MicroRNAs (miRNAs) act as tumour suppressor genes or oncogenes in the regulation of multiple carcinogenic processes. Aberrant miRNA expression is reported in Helicobacter pylori (H pylori)-related gastritis and gastric cancer. The cytotoxin-associated gene A (CagA) of H pylori has a pathophysiologically important role in gastric carcinogenesis. A study was undertaken to evaluate the effect of CagA on miRNA expression and its regulatory mechanism.

Methods The effect of CagA on miRNA expression was assessed by comprehensive miRNA microarray. The mechanisms of the in vitro and in vivo effects of CagA on histone modification and DNA methylation and the involvement of CagA-dysregulated signal transduction on let-7, an important representative miRNA in gastric carcinogenesis, were investigated.

Results In in vitro experiments, CagA significantly attenuated let-7 expression leading to Ras pathway activation. CagA enhanced c-myc, DNA methyltransferase 3B (DNMT3B) and Enhancer of Zeste homologue 2 (EZH2) expression and attenuated miR-26a and miR-101 expression, which resulted in the attenuation of let-7 expression by histone and DNA methylation. Experiments performed in CagA transgenic mice revealed that c-myc, EZH2 and DNMT3B expression were enhanced and let-7 expression was attenuated to induce Ras oncoprotein expression in the stomach, with no associated inflammation.

Conclusions H pylori CagA induces aberrant epigenetic silencing of let-7 expression, leading to Ras upregulation.

  • Helicobacter Pylori
  • Gastric Cancer
  • Methylation

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