MicroRNA-495-3p functions as a tumor suppressor by regulating multiple epigenetic modifiers in gastric carcinogenesis
MicroRNA-495-3p functions as a tumor suppressor by regulating multiple epigenetic modifiers in gastric carcinogenesis
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DOI：
10.1002/path.4994
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发表时间：
2018-01-01
影响因子：
7.3
通讯作者：
Nam, Suk Woo
中科院分区：
文献类型：
--
作者：
Eun, Jung Woo;Kim, Hyung Seok;Nam, Suk Woo
MicroRNAs （miRNAs）与控制转录组的机制进行复杂的相互作用，并同时靶向多个mrna。在这里，我们证明了microRNA-495-3p （miR-495-3p）作为一种有效的肿瘤抑制因子，通过控制胃癌发生过程中的十种致癌表观遗传修饰因子（EMs）。从癌症基因组图谱（TCGA）和国家生物技术信息中心（NCBI）基因表达图谱（GEO）提供的胃癌（GC）患者的大型队列转录组数据集中，我们能够总结出先前报道的51个与癌症进展有关的EMs中有15个在胃癌中显著过表达。计算靶标预测得到miR-495-3p，其靶向15种候选致癌em中的多达10种。miRNA模拟物在GC细胞中的异位表达导致miR-495-3p抑制10种EMs，并通过caspase依赖性和caspase非依赖性细胞死亡加工抑制肿瘤细胞的生长和增殖。此外，体外转移实验表明，miR-495-3p通过调节SLUG、vimentin和N-cadherin在GC细胞的转移行为中发挥作用。此外，用5-aza-2'-脱氧胞苷处理GC细胞可以恢复miR-495-3p的表达；序列分析显示GC细胞中miR-495-3p启动子区域存在高甲基化。提出了一个负调控环，其中DNMT1，在十个致癌的EMs中，通过miR-495-3p启动子的高甲基化调节miR-495-3p的表达。我们的研究结果表明，miR-495-3p的功能缺失或抑制会引发多种致癌em的过表达，从而促进胃上皮细胞的恶性转化和生长。版权所有(c) 2017英国和爱尔兰病理学会。约翰·威利父子有限公司出版。
MicroRNAs (miRNAs) engage in complex interactions with the machinery that controls the transcriptome and concurrently target multiple mRNAs. Here, we demonstrate that microRNA-495-3p (miR-495-3p) functions as a potent tumor suppressor by governing ten oncogenic epigenetic modifiers (EMs) in gastric carcinogenesis. From the large cohort transcriptome datasets of gastric cancer (GC) patients available from The Cancer Genome Atlas (TCGA) and the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO), we were able to recapitulate 15 EMs as significantly overexpressed in GC among the 51 EMs that were previously reported to be involved in cancer progression. Computational target prediction yielded miR-495-3p, which targets as many as ten of the 15 candidate oncogenic EMs. Ectopic expression of miRNA mimics in GC cells caused miR-495-3p to suppress ten EMs, and inhibited tumor cell growth and proliferation via caspase-dependent and caspase-independent cell death processing. In addition, in vitro metastasis assays showed that miR-495-3p plays a role in the metastatic behavior of GC cells by regulating SLUG, vimentin, and N-cadherin. Furthermore, treatment of GC cells with 5-aza-2'-deoxcytidine restored miR-495-3p expression; sequence analysis revealed hypermethylation of the miR-495-3p promoter region in GC cells. A negative regulatory loop is proposed, whereby DNMT1, among ten oncogenic EMs, regulates miR-495-3p expression via hypermethylation of the miR-495-3p promoter. Our findings suggest that the functional loss or suppression of miR-495-3p triggers overexpression of multiple oncogenic EMs, and thereby contributes to malignant transformation and growth of gastric epithelial cells. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.