Key Laboratory of Precision Oncology of Shandong Higher Education, Institute of precision medicine, Jining Medical University, Jining, Shandong 272067, PR China; Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, PR China.
Department of Neurosurgery, Second Hospital of Tianjin Medical University, Tianjin 300211, PR China.
Biochim Biophys Acta Gene Regul Mech. 2019 May;1862(5):567-581. doi: 10.1016/j.bbagrm.2019.02.003. Epub 2019 Feb 10.
MiR-15/16 play an important role in liver development and hepatocyte differentiation, but the mechanisms by which these miRNAs regulate their targets and downstream genes to influence cell fate are poorly understood. In this study, we showed up-regulation of miR-15/16 during HGF- and FGF4-induced hepatocyte differentiation from amniotic epithelial cells (AECs). To elucidate the role of miR-15/16 and their targets in hepatocyte differentiation, we investigated the roles of miR-15/16 in both the MAPK and Wnt/β-catenin pathways, which were predicted to be involved in miR-15/16 signaling. Our results demonstrated that the transcription of miR-15/16 was enhanced by c-Fos, c-Jun, and CREB, important elements of the MAPK pathway, and miR-15/16 in turn directly targeted adenomatous polyposis coli (APC) protein, a major member of the β-catenin degradation complex. MiR-15/16 destroyed these degradation complexes to activate β-catenin, and the activated β-catenin combined with LEF/TCF7L1 to form a transcriptional complex that enhanced transcription of hepatocyte nuclear factor 4 alpha (HNF4α). HNF4α also bound the promoter region of miR-15/16 and promoted its transcription, thereby forming a regulatory circuit to promote the differentiation of AECs into hepatocytes. Endogenous miRNAs are, therefore, involved in hepatocyte differentiation from AECs and should be considered during the development of an effective hepatocyte transplant therapy for liver damage.
miR-15/16 在肝发育和肝实质细胞分化中发挥重要作用，但这些 miRNA 调控其靶基因和下游基因以影响细胞命运的机制仍知之甚少。在这项研究中，我们发现 miR-15/16 在 HGF 和 FGF4 诱导的羊膜上皮细胞（AEC）向肝细胞分化过程中上调。为了阐明 miR-15/16 及其靶基因在肝细胞分化中的作用，我们研究了 miR-15/16 在 MAPK 和 Wnt/β-catenin 通路中的作用，这两条通路被预测参与了 miR-15/16 信号通路。我们的结果表明，miR-15/16 的转录受到 MAPK 通路的重要元件 c-Fos、c-Jun 和 CREB 的增强，miR-15/16 反过来又直接靶向 APC 蛋白，即β-catenin 降解复合物的主要成员。miR-15/16 破坏这些降解复合物以激活β-catenin，而激活的β-catenin 与 LEF/TCF7L1 结合形成转录复合物，增强肝细胞核因子 4α（HNF4α）的转录。HNF4α 也结合 miR-15/16 的启动子区域并促进其转录，从而形成一个调控回路，促进 AEC 向肝细胞分化。因此，内源性 miRNAs 参与了 AEC 向肝细胞的分化，在开发有效的肝细胞移植治疗肝损伤的过程中应予以考虑。
