Journal Article

Methylation-associated silencing of microRNA-34b/c in gastric cancer and its involvement in an epigenetic field defect

Hiromu Suzuki, Eiichiro Yamamoto, Masanori Nojima, Masahiro Kai, Hiro-o Yamano, Kenjiro Yoshikawa, Tomoaki Kimura, Toyoki Kudo, Eiji Harada, Tamotsu Sugai, Hiroyuki Takamaru, Takeshi Niinuma, Reo Maruyama, Hiroyuki Yamamoto, Takashi Tokino, Kohzoh Imai, Minoru Toyota and Yasuhisa Shinomura

in Carcinogenesis

Volume 31, issue 12, pages 2066-2073
Published in print December 2010 | ISSN: 0143-3334
Published online October 2010 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgq203
Methylation-associated silencing of microRNA-34b/c in gastric cancer and its involvement in an epigenetic field defect

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Altered expression of microRNA (miRNA) is strongly implicated in cancer, and recent studies have shown that the silencing of some miRNAs is associated with CpG island hypermethylation. To identify epigenetically silenced miRNAs in gastric cancer (GC), we screened for miRNAs induced by treatment with 5-aza-2’-deoxycytidine and 4-phenylbutyrate. We found that miR-34b and miR-34c are epigenetically silenced in GC and that their downregulation is associated with hypermethylation of the neighboring CpG island. Methylation of the miR-34b/c CpG island was frequently observed in GC cell lines (13/13, 100%) but not in normal gastric mucosa from Helicobacter pylori-negative healthy individuals. Transfection of a precursor of miR-34b and miR-34c into GC cells induced growth suppression and dramatically changed the gene expression profile. Methylation of miR-34b/c was found in a majority of primary GC specimens (83/118, 70%). Notably, analysis of non-cancerous gastric mucosae from GC patients (n = 109) and healthy individuals (n = 85) revealed that methylation levels are higher in gastric mucosae from patients with multiple GC than in mucosae from patients with single GC (27.3 versus 20.8%; P < 0.001) or mucosae from H. pylori-positive healthy individuals (27.3 versus 20.7%; P < 0.001). These results suggest that miR-34b and miR-34c are novel tumor suppressors frequently silenced by DNA methylation in GC, that methylation of miR-34b/c is involved in an epigenetic field defect and that the methylation might be a predictive marker of GC risk.

Journal Article.  5839 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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