Division of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
J Cell Mol Med. 2021 Jun;25(11):5220-5237. doi: 10.1111/jcmm.16530. Epub 2021 May 5.
MicroRNAs have emerged as essential regulators in the biological process of liver regeneration by modulating the post-transcriptional expression of the target genes. In the present study, we found miR-20a expression is decreased remarkably in three rodent liver regeneration models using miRNA PCR array and Venn diagram analysis. Inhibition of miR-20a expression enhanced hepatocytes proliferation in vivo and in vitro. In contrast, overexpression of miR-20a reduces hepatocytes proliferation and subsequently impaired liver regeneration in the mouse PHx model. Moreover, we have identified TCF4 as a target gene of miR-20a using the PCR Array and luciferase assay. Next, mice with TCF4 deficiency were used to establish the PHx model and subjected to the examination of liver regeneration capacity. We found TCF4-deficient mice exhibited impaired liver regeneration compared with control. Given that TCF4 acts as a transcription factor, we sort to elucidate the downstream genes involved in liver regeneration. Promoter analysis and Chip assay confirmed that TCF4 enhances CDC2 and CDC6 expression through binding to the promoter region and leads to the proliferation and cell cycle progression in hepatocytes. In conclusion, this study provides evidence that the miR20a-TCF4-CDC2/6 axis plays an essential role during liver regeneration.
微小 RNA 通过调节靶基因的转录后表达，成为肝脏再生生物学过程中的重要调节因子。在本研究中，我们使用 miRNA PCR 阵列和 Venn 图分析发现，三种啮齿动物肝脏再生模型中 miR-20a 的表达显著降低。抑制 miR-20a 的表达可增强体内和体外肝细胞的增殖。相比之下，miR-20a 的过表达会减少肝细胞的增殖，随后损害小鼠 PHx 模型中的肝脏再生。此外，我们还使用 PCR 阵列和荧光素酶测定法鉴定了 TCF4 是 miR-20a 的靶基因。接下来，使用 TCF4 缺陷小鼠建立 PHx 模型并进行肝脏再生能力的检测。我们发现 TCF4 缺陷小鼠的肝脏再生能力与对照组相比受损。鉴于 TCF4 作为转录因子发挥作用，我们试图阐明参与肝脏再生的下游基因。启动子分析和 Chip 测定证实 TCF4 通过结合启动子区域增强 CDC2 和 CDC6 的表达，从而导致肝细胞的增殖和细胞周期进程。总之，本研究提供了证据表明 miR20a-TCF4-CDC2/6 轴在肝脏再生过程中起着重要作用。
