miR-148a plays a pivotal role in the liver by promoting the hepatospecific phenotype and suppressing the invasiveness of transformed cells

Abstract

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. Conclusion: 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. (Hepatology 2013;53:1153–1165)

Characterization of exosomal RNAs derived from human gastric cancer cells by deep sequencing

“…36 Generally, miR-148a functions as a tumor suppressor in cancer cells. [33][34][35][36] However, in most studies, miR-148a was detected in specimens of tissues or cell lines. There is limited research involving exosomes containing miR-148a.…”

“…miR-148a is downregulated in several types of tumors, including glioblastoma, 32 hepatocellular carcinoma, 33,34 colorectal cancer, 35 and GC. 36 Generally, miR-148a functions as a tumor suppressor in cancer cells.…”

Function and clinical potential of microRNAs in hepatocellular carcinoma

“…Furthermore, miR122 forms a positive feedback loop with FOXA1 and HNF4α to regulate hepatocyte maturation (34). Several other miRNAs are involved in the regulation of liver development and differentiation, including miR148a (35) and miR33 (36).…”

Epigenetic regulation of hepatic tumor-initiating cells

“…MiR-148a directly regulated DNMT-1 expression by complementary binding to its 3'-UTR element. In Hepa 1-6 hepatoma cells, miR-148a suppressed invasive properties of HCC cells by indirectly inhibiting hepatocyte growth factor receptor (c-Met) (103). As IL-6 increased the expression of DNMT-1 through miR-148a in human cholangiocarcinoma cell lines, miR-148a provides a link between inflammation-associated cytokine and oncogenesis in cholangiocarcinoma (104).…”