RT Journal Article SR Electronic T1 CagA mediates epigenetic regulation to attenuate let-7 expression in Helicobacter pylori-related carcinogenesis JF Gut JO Gut FD BMJ Publishing Group Ltd and British Society of Gastroenterology SP 1536 OP 1546 DO 10.1136/gutjnl-2011-301625 VO 62 IS 11 A1 Hayashi, Yoshito A1 Tsujii, Masahiko A1 Wang, Jun A1 Kondo, Jumpei A1 Akasaka, Tomofumi A1 Jin, Ying A1 Li, Wei A1 Nakamura, Toru A1 Nishida, Tsutomu A1 Iijima, Hideki A1 Tsuji, Shingo A1 Kawano, Sunao A1 Hayashi, Norio A1 Takehara, Tetsuo YR 2013 UL http://gut.bmj.com/content/62/11/1536.abstract AB 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.