MicroRNAs control hepatocyte proliferation during liver regeneration.
MicroRNAs control hepatocyte proliferation during liver regeneration.
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DOI：
10.1002/hep.23547
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发表时间：
2010-05
期刊：
影响因子：
13.5
通讯作者：
Willenbring, Holger
中科院分区：
文献类型：
--
作者：
Song, Guisheng;Sharma, Amar Deep;Roll, Garrett R.;Ng, Raymond;Lee, Andrew Y.;Blelloch, Robert H.;Frandsen, Niels M.;Willenbring, Holger
microRNAs（miRNAs）是一类新的基因表达调控因子。在其他作用中，miRNAs已被证明在发育和癌症中控制细胞增殖。然而，miRNAs是否在肝再生过程中调节肝细胞增殖尚不清楚。我们通过对DiGeorge综合征关键区基因8（DGCR 8）（miRNA加工途径的重要组成部分）肝细胞特异性失活的小鼠进行2/3部分肝切除术（2/3 PH）来解决这个问题。这些小鼠的肝细胞是miRNA缺陷的，并表现出细胞周期进展的延迟，涉及G1期到S期的转变。2/3 PH后野生型小鼠肝脏的检查揭示了一个miRNA亚组的差异表达，特别是miR-21的诱导和miR-378的抑制。我们进一步发现，miR-21直接抑制Btg 2，Btg 2是一种细胞周期抑制剂，可防止2/3 PH后肝细胞DNA合成所必需的叉头框M1（FoxM 1）活化。此外，我们发现miR-378直接抑制鸟氨酸脱羧酶（Odc 1），我们的研究结果表明，miRNAs是肝再生过程中肝细胞增殖的关键调节因子。由于这些miRNAs和靶基因的相互作用是保守的，我们的发现也可能与人类肝脏再生有关。
MicroRNAs (miRNAs) constitute a new class of regulators of gene expression. Among other actions, miRNAs have been shown to control cell proliferation in development and cancer. However, whether miRNAs regulate hepatocyte proliferation during liver regeneration is unknown. We addressed this question by performing 2/3 partial hepatectomy (2/3 PH) on mice with hepatocyte-specific inactivation of DiGeorge syndrome critical region gene 8 (DGCR8), an essential component of the miRNA processing pathway. Hepatocytes of these mice were miRNA-deficient and exhibited a delay in cell cycle progression involving the G1 to S phase transition. Examination of livers of wildtype mice after 2/3 PH revealed differential expression of a subset of miRNAs, notably an induction of miR-21 and repression of miR-378. We further discovered that miR-21 directly inhibits Btg2, a cell cycle inhibitor that prevents activation of forkhead box M1 (FoxM1), which is essential for DNA synthesis in hepatocytes after 2/3 PH. In addition, we found that miR-378 directly inhibits ornithine decarboxylase (Odc1), which is known to promote DNA synthesis in hepatocytes after 2/3 PH. Our results show that miRNAs are critical regulators of hepatocyte proliferation during liver regeneration. Because these miRNAs and target gene interactions are conserved, our findings may also be relevant to human liver regeneration.
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