Methylation-associated silencing of microRNA-34b/c in gastric cancer and its involvement in an epigenetic field defect
Methylation-associated silencing of microRNA-34b/c in gastric cancer and its involvement in an epigenetic field defect
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DOI：
10.1093/carcin/bgq203
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发表时间：
2010-12-01
期刊：
影响因子：
4.7
通讯作者：
Shinomura, Yasuhisa
中科院分区：
文献类型：
--
作者：
Suzuki, Hiromu;Yamamoto, Eiichiro;Shinomura, Yasuhisa
microRNA (miRNA) 表达的改变与癌症密切相关，最近的研究表明，一些 miRNA 的沉默与 CpG 岛高甲基化有关。为了鉴定胃癌 (GC) 中表观遗传沉默的 miRNA，我们筛选了由 5-aza-2'-脱氧胞苷和 4-苯基丁酸治疗诱导的 miRNA。我们发现 miR-34b 和 miR-34c 在 GC 中表观遗传沉默，并且它们的下调与邻近 CpG 岛的高甲基化相关。 miR-34b/c CpG 岛的甲基化经常在 GC 细胞系中观察到（13/13，100%），但在幽门螺杆菌阴性健康个体的正常胃粘膜中没有观察到。将 miR-34b 和 miR-34c 前体转染 GC 细胞可诱导生长抑制并显着改变基因表达谱。在大多数原代 GC 标本中发现了 miR-34b/c 的甲基化（83/118，70%）。值得注意的是，对 GC 患者 (n = 109) 和健康个体 (n = 85) 的非癌性胃粘膜的分析显示，多次 GC 患者的胃粘膜甲基化水平高于单次 GC 患者的胃粘膜（27.3 vs 20.8%；P < 0.001）或幽门螺杆菌阳性健康个体的粘膜（27.3 vs 20.7%；P < 0.001）。 0.001）。这些结果表明，miR-34b 和 miR-34c 是新型肿瘤抑制因子，经常被 GC 中的 DNA 甲基化沉默，miR-34b/c 的甲基化涉及表观遗传领域缺陷，并且甲基化可能是 GC 风险的预测标志物。
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.