Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan.
Hepatology. 2013 Sep;58(3):1153-65. doi: 10.1002/hep.26422. Epub 2013 Jul 30.
MicroRNAs (miRNAs) are evolutionary conserved small RNAs that post-transcriptionally regulate the expression of target genes. To date, the role of miRNAs in liver development is not fully understood. By using an experimental model that allows the induced and controlled differentiation of mouse fetal hepatoblasts (MFHs) into mature hepatocytes, we identified miR-148a as a hepatospecific miRNA highly expressed in adult liver. The main finding of this study revealed that miR-148a was critical for hepatic differentiation through the direct targeting of DNA methyltransferase (DNMT) 1, a major enzyme responsible for epigenetic silencing, thereby allowing the promotion of the "adult liver" phenotype. It was also confirmed that the reduction of DNMT1 by RNA interference significantly promoted the expression of the major hepatic biomarkers. In addition to the essential role of miR-148a in hepatocyte maturation, we identified its beneficial effect through the repression of hepatocellular carcinoma (HCC) cell malignancy. miR-148a expression was frequently down-regulated in biopsies of HCC patients as well as in mouse and human HCC cell lines. Overexpressing miR-148a led to an enhancement of albumin production and a drastic inhibition of the invasive properties of HCC cells, whereas miR-148a silencing had the opposite consequences. Finally, we showed that miR-148a exerted its tumor-suppressive effect by regulating the c-Met oncogene, regardless of the DNMT1 expression level.
miR-148a is essential for the physiology of the liver because it promotes the hepatospecific phenotype and acts as a tumor suppressor. Most important, this report is the first to demonstrate a functional role for a specific miRNA in liver development through regulation of the DNMT1 enzyme.
microRNAs(miRNAs) 是进化上保守的小 RNA，可在后转录水平调节靶基因的表达。迄今为止，miRNAs 在肝脏发育中的作用尚不完全清楚。通过使用一种允许诱导和控制小鼠胎儿肝细胞(mHFs)分化为成熟肝细胞的实验模型，我们鉴定出 miR-148a 是一种在成年肝脏中高度表达的肝特异性 miRNA。本研究的主要发现揭示了 miR-148a 通过直接靶向 DNA 甲基转移酶(DNMT)1 对肝分化至关重要，DNMT1 是负责表观遗传沉默的主要酶，从而促进了“成年肝脏”表型的出现。还证实了 RNA 干扰降低 DNMT1 显著促进了主要肝生物标志物的表达。除了 miR-148a 在肝细胞成熟中的重要作用外，我们还通过抑制肝癌(HCC)细胞的恶性肿瘤证实了其有益作用。miR-148a 在 HCC 患者活检以及小鼠和人 HCC 细胞系中表达经常下调。过表达 miR-148a 导致白蛋白产生增强和 HCC 细胞侵袭性的急剧抑制，而 miR-148a 沉默则产生相反的后果。最后，我们表明，miR-148a 通过调节 c-Met 癌基因发挥其肿瘤抑制作用，而与 DNMT1 表达水平无关。
miR-148a 对肝脏的生理功能至关重要，因为它促进了肝特异性表型，并作为一种肿瘤抑制因子。最重要的是，本报告首次证明了一种特定的 miRNA 通过调节 DNMT1 酶在肝脏发育中的功能作用。
