Down-Regulation of microRNA-26a Promotes Mouse Hepatocyte Proliferation during Liver Regeneration

Abstract

BackgroundInadequate liver regeneration (LR) is still an unsolved problem in major liver resection and small-for-size syndrome post-living donor liver transplantation. A number of microRNAs have been shown to play important roles in cell proliferation. Herein, we investigated the role of miR-26a as a pivotal regulator of hepatocyte proliferation in LR.Methodology/Principal FindingsAdult male C57BL/6J mice, undergoing 70% partial hepatectomy (PH), were treated with Ad5-anti-miR-26a-LUC or Ad5-miR-26a-LUC or Ad5-LUC vector via portal vein. The animals were subjected to in vivo bioluminescence imaging. Serum and liver samples were collected to test liver function, calculate liver-to-body weight ratio (LBWR), document hepatocyte proliferation (Ki-67 staining), and investigate potential targeted gene expression of miR-26a by quantitative real-time PCR and Western blot. The miR-26a level declined during LR after 70% PH. Down-regulation of miR-26a by anti-miR-26a expression led to enhanced proliferation of hepatocytes, and both LBWR and hepatocyte proliferation (Ki-67+ cells %) showed an increased tendency, while liver damage, indicated by aspartate aminotransferase (AST), alanine aminotransferase (ALT) and total bilirubin (T-Bil), was reduced. Furthermore, CCND2 and CCNE2, as possible targeted genes of miR-26a, were up-regulated. In addition, miR-26a over-expression showed converse results.Conclusions/SignificanceMiR-26a plays crucial role in regulating the proliferative phase of LR, probably by repressing expressions of cell cycle proteins CCND2 and CCNE2. The current study reveals a novel miRNA-mediated regulation pattern during the proliferative phase of LR.

Identification of target genes for adenohypophysis-prefer miR-7 and miR-375 in cattle

“…Therefore, in this experiment, the expression of miRNAs in bovine pituitary was examined to determine which gene regulates pituitary development. Comprehensive analysis of the results using various software programs can improve the prediction accuracy of candidate miRNA target genes (Zhou et al, 2012;Altmäe et al, 2012).…”

Complexity of microRNA function and the role of isomiRs in lipid homeostasis

“…For example, critical lipid-sensitive transcription factors controlling hepatic metabolism, such as the LXR and PPAR families, have been shown to be functional targets of multiple miRNAs (LXR ␣ : miR-613; PPAR ␣ : miR-21, miR-10b, miR-141; PPAR ␥ : miR-23a, miR-27b, miR-130) ( 85,(94)(95)(96)(97)(98)(99). Moreover, complex feedback loops between transcription factors and miRNAs appear to control hepatocyte differentiation and possibly other aspects of liver biology (100)(101)(102). Several other canonical miRNAs have been shown to infl uence lipid metabolic pathways, including miR-122, miR-370, miR-378, and miR-758, and they are comprehensively discussed in numerous recent review articles ( 43-45, 94, 103 ).…”

MicroRNAs in Liver Regeneration

“…Several studies have shown that miR-26a family members could suppress tumorigenesis in liver cancer cells and B lymphoma cells, and expression of miR-26a was also found to be significantly declined after 70% PH [39]. Adenovirusin 5 (Ad5)-anti-miR-26a-LUC was utilized to downregulate miR-26a in the mouse liver which resulted in enhanced proliferation of hepatocytes and improved liver function characterized by reduced serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and total bilirubin (T-Bil) during PH.…”