Epigenetic Silencing of miR-490-3p Reactivates the Chromatin Remodeler SMARCD1 to Promote Helicobacter pylori-Induced Gastric Carcinogenesis
Epigenetic Silencing of miR-490-3p Reactivates the Chromatin Remodeler SMARCD1 to Promote Helicobacter pylori-Induced Gastric Carcinogenesis
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DOI：
10.1158/0008-5472.can-14-1301
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发表时间：
2015-02-15
期刊：
影响因子：
11.2
通讯作者：
Cho, Chi H.
中科院分区：
文献类型：
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作者：
Shen, Jing;Xiao, Zhangang;Cho, Chi H.
染色质重塑已成为胃癌的一个标志，但染色质调节基因以外的其他调控尚不清楚。幽门螺杆菌引起的表观遗传失调促进胃癌的发生，但microRNA（miRNA）在这一多阶段级联反应中的作用和功能尚未完全阐明。在本研究中，miRNA在H. pylori和N-甲基-N-亚硝基脲（MNU）的miRNA表达谱。miR-490- 3 p在H. pylori和MNU诱导的胃癌发生。miR-490- 3 p在人胃癌组织中被证实显著下调，其中发现其调控区被高甲基化。miR-490- 3 p通过直接靶向SWItch/Sucrose NonFermentable（SWI/SNF）染色质重塑复合物亚基SMARD 1，对胃癌细胞发挥生长和转移抑制作用。SMARD 1的敲低显著减弱了miR-490- 3 p抑制剂的促肿瘤作用，而SMARD 1的增强表达促进了胃癌细胞的体外和体内致癌表型。SMARD 1在胃癌中显著上调，其高表达与TNM分期无关的患者生存期缩短相关。总之，高甲基化介导的miR-490- 3 p沉默重新激活SMARD 1，赋予恶性表型，机械连接H。幽门螺杆菌、染色质重塑和胃癌发生。（C）2014年AACR。
Chromatin remodeling has emerged as a hallmark of gastric cancer, but the regulation of chromatin regulators other than genetic change is unknown. Helicobacter pylori causes epigenetic dysregulation to promote gastric carcinogenesis, but the roles and functions of microRNAs (miRNA) in this multistage cascade are not fully explored. In this study, miRNA expression in preneoplastic and neoplastic lesions in murine stomachs induced by H. pylori and N-methyl-N-nitrosourea (MNU) was profiled by miRNA expression array. miR-490-3p exhibited progressive downregulation in gastritis, intestinal metaplasia, and adenocarcinoma during H. pylori and MNU-induced gastric carcinogenesis. Significant downregulation of miR-490-3p was confirmed in human gastric cancer tissues in which its regulatory region was found to be hypermethylated. miR-490-3p exerted growth- and metastasis-suppressive effects on gastric cancer cells through directly targeting SMARCD1, a SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex subunit. Knockdown of SMARCD1 significantly attenuated the protumorigenic effects of miR-490-3p inhibitor, whereas enforced expression of SMARCD1 promoted in vitro and in vivo oncogenic phenotypes of gastric cancer cells. SMARCD1 was markedly upregulated in gastric cancer in which its high expression was associated with shortened patients' survival independent of TNM staging. In conclusion, hypermethylation-mediated silencing of miR-490-3p reactivates SMARCD1 to confer malignant phenotypes, mechanistically linking H. pylori, chromatin remodeling, and gastric carcinogenesis. (C)2014 AACR.