Lim Byungho, Kim Hee-Jin, Heo Haejeong, Huh Nanhyung, Baek Su-Jin, Kim Jong-Hwan, Bae Dong-Hyuck, Seo Eun-Hye, Lee Sang-Il, Song Kyu-Sang, Kim Seon-Young, Kim Yong Sung, Kim Mirang
Division of Drug Discovery Research, Research Center for Drug Discovery Technology, Korea Research Institute of Chemical Technology, Daejeon, Korea.
Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea.
Cancer Med. 2018 Jul;7(7):3411-3424. doi: 10.1002/cam4.1605. Epub 2018 Jun 4.
Epigenetic dysregulation is a major driver of tumorigenesis. To identify tumor-suppressive microRNAs repressed by DNA methylation in gastric cancer (GC), we analyzed the genome-wide DNA methylation and microRNA expression profiles of EpCAM+/CD44+ GC cells. Among the set of microRNAs screened, miR-1271 was identified as a microRNA repressed by DNA methylation in GC. Forced miR-1271 expression substantially suppressed the growth, migration, and invasion of GC cells. To identify candidate target genes and signaling pathways regulated by miR-1271, we performed RNA sequencing. Among the genes down-regulated by miR-1271, MAP2K1 (MEK1) was significantly repressed by miR-1271, and the associated ERK/MAPK signaling pathway was also inhibited. TEAD4 was also repressed by miR-1271, and the associated YAP1 signatures within genes regulated by miR-1271 were significantly enriched. These findings uncovered MEK1 and TEAD4 as novel miR-1271 targets and suggest that the epigenetic silencing of miR-1271 is crucial for GC development.
表观遗传失调是肿瘤发生的主要驱动因素。为了鉴定胃癌（GC）中被DNA甲基化抑制的肿瘤抑制性微小RNA，我们分析了EpCAM+/CD44+ GC细胞的全基因组DNA甲基化和微小RNA表达谱。在筛选出的微小RNA集合中，miR-1271被鉴定为GC中被DNA甲基化抑制的微小RNA。强制表达miR-1271可显著抑制GC细胞的生长、迁移和侵袭。为了鉴定受miR-1271调控的候选靶基因和信号通路，我们进行了RNA测序。在被miR-1271下调的基因中，MAP2K1（MEK1）被miR-1271显著抑制，相关的ERK/MAPK信号通路也被抑制。TEAD4也被miR-1271抑制，并且在受miR-1271调控的基因中相关的YAP1特征显著富集。这些发现揭示了MEK1和TEAD4是新的miR-1271靶标，并表明miR-1271的表观遗传沉默对GC的发展至关重要。
