MiR-15/16 mediate crosstalk between the MAPK and Wnt/β-catenin pathways during hepatocyte differentiation from amniotic epithelial cells
MiR-15/16 mediate crosstalk between the MAPK and Wnt/β-catenin pathways during hepatocyte differentiation from amniotic epithelial cells
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MiR-15/16 在羊膜上皮细胞分化肝细胞过程中介导 MAPK 和 Wnt/β-catenin 通路之间的串扰
DOI：
10.1016/j.bbagrm.2019.02.003
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发表时间：
2019-05-01
影响因子：
4.7
通讯作者：
Gao, Yuhua
中科院分区：
文献类型：
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作者：
Bai, Chunyu;Zhang, Hongwei;Gao, Yuhua
MiR-15/16在肝脏发育和肝细胞分化中起重要作用，但这些miRNAs调节其靶基因和下游基因以影响细胞命运的机制知之甚少。在这项研究中，我们发现在HGF和FGF 4诱导的羊膜上皮细胞（AEC）肝细胞分化过程中，miR-15/16表达上调。为了阐明miR-15/16及其靶点在肝细胞分化中的作用，我们研究了miR-15/16在MAPK和Wnt/β-catenin途径中的作用，这些途径被预测参与miR-15/16信号传导。我们的研究结果表明，miR-15/16的转录被MAPK通路的重要元件c-Fos、c-Jun和CREB增强，而miR-15/16又直接靶向大肠腺瘤性息肉病（APC）蛋白，APC蛋白是β-连环蛋白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-连环蛋白，并且激活的β-连环蛋白与LEF/TCF 7 L1结合以形成增强肝细胞核因子4 α（HNF 4 α）转录的转录复合物。HNF 4 α还结合miR-15/16的启动子区并促进其转录，从而形成促进AEC分化为肝细胞的调节回路。因此，内源性miRNAs参与了AEC的肝细胞分化，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。
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/beta-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 beta-catenin degradation complex. MiR-15/16 destroyed these degradation complexes to activate beta-catenin, and the activated beta-catenin combined with LEF/TCF7L1 to form a transcriptional complex that enhanced transcription of hepatocyte nuclear factor 4 alpha (HNF4 alpha). HNF4 alpha 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.