title: CagA mediates epigenetic regulation to attenuate let-7 expression in Helicobacter pylori-related carcinogenesis.
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.
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Masahiko
authors.initials: M
authors.lastname: Tsujii
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Jumpei
authors.initials: J
authors.lastname: Kondo
authors.forename: Tomofumi
authors.initials: T
authors.lastname: Akasaka
authors.forename: Ying
authors.initials: Y
authors.lastname: Jin
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Toru
authors.initials: T
authors.lastname: Nakamura
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nishida
authors.forename: Hideki
authors.initials: H
authors.lastname: Iijima
authors.forename: Shingo
authors.initials: S
authors.lastname: Tsuji
authors.forename: Sunao
authors.initials: S
authors.lastname: Kawano
authors.forename: Norio
authors.initials: N
authors.lastname: Hayashi
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takehara
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000096:biosynthesis / Q000235:genetics*; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000235:genetics*; D063646:Carcinogenesis / Q000235:genetics*; D019175:DNA Methylation; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D004847:Epithelial Cells / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D020868:Gene Silencing; D005798:Genes, Bacterial; D016481:Helicobacter Infections / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D016480:Helicobacter pylori / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D063151:Polycomb Repressive Complex 2 / Q000096:biosynthesis; D051381:Rats; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000382:microbiology*; D018631:ras Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D035683:MicroRNAs; C080866:cagA protein, Helicobacter pylori; C542687:mirnlet7 microRNA, mouse; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2; D018631:ras Proteins