School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong. Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong.
Cancer Res. 2015 Feb 15;75(4):754-65. doi: 10.1158/0008-5472.CAN-14-1301. Epub 2014 Dec 12.
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.
染色质重塑已成为胃癌的一个标志，但除遗传改变之外，对染色质调节因子的调控尚不清楚。幽门螺杆菌引起表观遗传失调，促进胃致癌作用，但 miRNA（miRNA）在这一多步骤级联反应中的作用和功能尚未充分探索。在这项研究中，通过 miRNA 表达阵列对幽门螺杆菌和 N-甲基-N-亚硝脲（MNU）诱导的小鼠胃前瘤和肿瘤病变中的 miRNA 表达进行了分析。miR-490-3p 在幽门螺杆菌和 MNU 诱导的胃癌发生过程中，在胃炎、肠上皮化生和腺癌中表现出逐渐下调。在人胃癌组织中，miR-490-3p 的调控区被发现超甲基化，其表达显著下调。miR-490-3p 通过直接靶向 SMARCD1（SWItch/Sucrose NonFermentable（SWI/SNF）染色质重塑复合物亚基），对胃癌细胞的生长和转移具有抑制作用。SMARCD1 的敲低显著减弱了 miR-490-3p 抑制剂的促肿瘤作用，而 SMARCD1 的强制表达促进了胃癌细胞的体外和体内致癌表型。SMARCD1 在胃癌中明显上调，其高表达与 TNM 分期无关，与患者生存时间缩短有关。总之，miR-490-3p 的高甲基化介导沉默重新激活 SMARCD1，赋予恶性表型，从而在机制上连接了幽门螺杆菌、染色质重塑和胃癌发生。
