Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan.
Liver Cancer Prevention Research Unit, RIKEN Center for Integrative Medical Sciences, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan.
Cell Death Dis. 2019 Jul 18;10(8):553. doi: 10.1038/s41419-019-1788-6.
Numerous studies have described the critical role played by microRNAs (miRNAs) in cancer progression and the potential of these small non-coding RNAs for diagnostic or therapeutic applications. However, the mechanisms responsible for the altered expression of miRNAs in malignant cells remain poorly understood. Herein, via epigenetic unmasking, we identified a group of miRNAs located in the imprinted delta like non-canonical Notch ligand 1 (DLK1)-maternally expressed 3 (MEG3) locus that were repressed in hepatic tumor cells. Notably, miR-493-5p epigenetic silencing was correlated with hypermethylation of the MEG3 differentially regulated region (DMR) in liver cancer cell lines and tumor tissues from patients. Experimental rescue of miR-493-5p promoted an anti-cancer response by hindering hepatocellular carcinoma (HCC) cell growth in vitro and tumor progression in vivo. We found that miR-493-5p mediated part of its tumor-suppressor activity by abrogating overexpression of insulin-like growth factor 2 (IGF2) and the IGF2-derived intronic oncomir miR-483-3p in HCC cells characterized by IGF2 loss of imprinting (LOI). In summary, this study describes an unknown miRNA-dependent regulatory mechanism between two distinct imprinted loci and a possible therapeutic window for liver cancer patients exhibiting IGF2-miR-483 LOI and amplification.
许多研究描述了 microRNAs（miRNAs）在癌症进展中所起的关键作用，以及这些小非编码 RNA 用于诊断或治疗应用的潜力。然而，导致恶性细胞中 miRNA 表达改变的机制仍知之甚少。在此，我们通过表观遗传揭示，鉴定了一组位于印记 delta 样非经典 Notch 配体 1（DLK1）-母系表达 3（MEG3）基因座中的 miRNAs，这些 miRNAs 在肝肿瘤细胞中受到抑制。值得注意的是，miR-493-5p 的表观遗传沉默与肝癌细胞系和患者肿瘤组织中 MEG3 差异调控区（DMR）的高甲基化相关。实验性恢复 miR-493-5p 的表达通过抑制体外肝癌细胞（HCC）生长和体内肿瘤进展，促进了抗癌反应。我们发现，miR-493-5p 通过消除胰岛素样生长因子 2（IGF2）的过表达及其在 HCC 细胞中的 IGF2 衍生内含子致癌 miRNA miR-483-3p 的表达，部分发挥其肿瘤抑制活性，这些 HCC 细胞表现出 IGF2 印记丢失（LOI）。总之，这项研究描述了两个不同印记基因座之间未知的 miRNA 依赖性调节机制，以及可能为表现出 IGF2-miR-483 LOI 和扩增的肝癌患者提供治疗窗口。
