Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, Southern Medical University , Guangzhou , China.
Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University , Guangzhou , China.
Am J Physiol Gastrointest Liver Physiol. 2018 Oct 1;315(4):G443-G453. doi: 10.1152/ajpgi.00072.2018. Epub 2018 May 24.
Liver regeneration after two-thirds partial hepatectomy (PH) is a clinically significant repair process for restoring proper liver architecture. Although microRNA-155 (miR-155) has been found to serve as a crucial microRNA regulator that controls liver cell function and proliferation, little is known about its specific role in the regenerating liver. Using a mouse model with miR-155 overexpression or miR-155 knockout, we investigated the molecular mechanisms of miR-155 in liver regeneration. We found a marked induction of miR-155 in C57BL/6 mice after PH. Furthermore, RL-m155 mice showed enhanced liver regeneration as a result of accelerated progression of hepatocytes into the cell cycle, mainly through an increase in cyclin levels. However, proliferation of hepatocytes was delayed in miR-155-deficient livers. Expression of suppressor of cytokine signaling 1 (SOCS1) was dramatically downregulated in the process of liver regeneration, and enhancement of SOCS1 contributed to impaired proliferation of hepatocytes. Additionally, in vitro and in vivo experiments showed that adenovirus- or adeno-associated virus-mediated overexpression of SOCS1 attenuated improved liver regeneration induced by miR-155 overexpression. Our study shows that miR-155 is a pro-proliferative regulator in liver regeneration by facilitating the cell cycle and directly targeting SOCS1. NEW & NOTEWORTHY Our findings suggest a microRNA-155 (miR-155)-mediated positive regulation pattern in liver regeneration. A series of in vivo and in vitro studies showed that miR-155 upregulation enhanced partial hepatectomy-induced proliferation of hepatocytes by promoting the cell cycle without inducing DNA damage or apoptosis. Suppressor of cytokine signaling 1, a target gene of miR-155, antagonized the proliferation-promoting effect of miR-155. Therefore, pharmacological intervention targeting miR-155 may be therapeutically beneficial in various liver diseases.
肝部分切除术（PH）后三分之二的肝再生是一种临床上重要的修复过程，可恢复肝脏的正常结构。虽然 microRNA-155（miR-155）已被发现是控制肝细胞功能和增殖的关键 miRNA 调节剂，但它在再生肝脏中的具体作用知之甚少。我们使用 miR-155 过表达或 miR-155 敲除的小鼠模型，研究了 miR-155 在肝再生中的分子机制。我们发现 PH 后 C57BL/6 小鼠中 miR-155 的表达明显上调。此外，由于肝细胞进入细胞周期的速度加快，RL-m155 小鼠的肝再生增强，主要是通过 cyclin 水平的增加。然而，miR-155 缺失的肝脏中肝细胞的增殖被延迟。在肝再生过程中，细胞因子信号转导抑制因子 1（SOCS1）的表达明显下调，SOCS1 的增强导致肝细胞增殖受损。此外，体内外实验表明，腺病毒或腺相关病毒介导的 SOCS1 过表达可减弱 miR-155 过表达诱导的肝再生改善。我们的研究表明，miR-155 通过促进细胞周期直接靶向 SOCS1，是肝再生中的促增殖调节剂。本研究揭示了 miR-155 在肝再生中的正调控模式。一系列体内外研究表明，miR-155 上调通过促进细胞周期而不诱导 DNA 损伤或细胞凋亡来增强部分肝切除诱导的肝细胞增殖。miR-155 的靶基因细胞因子信号转导抑制因子 1（SOCS1）拮抗 miR-155 的促增殖作用。因此，针对 miR-155 的药物干预可能在各种肝脏疾病中具有治疗益处。
