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.
Highlights
After 70% partial hepatectomy (PH) in mice, the residual liver is unique in its intrinsic ability to regenerate to restore its original mass and function within 7–10 days in a process called liver regeneration (LR) [1,2,3,4,5,6]
The miR-26a levels declined during LR after 70% PH, as observed in the regenerating mouse liver compared with sham operation (SH) group
This difference was most significant at 120 h after PH, when the miR-26a expression showed a 3-fold reduction compared to SH group (P,0.01) (Figure 1)
Summary
After 70% partial hepatectomy (PH) in mice, the residual liver is unique in its intrinsic ability to regenerate to restore its original mass and function within 7–10 days in a process called liver regeneration (LR) [1,2,3,4,5,6]. Several studies have shown the critical role of miRNAs in liver regeneration. Kota J et al have shown that miR-26a presented with an antiproliferative property in human liver cancer [15], and another study showed that miR-26a family members suppressed tumorigenesis in B lymphoma cells [17]. These reports promote us to investigate the role of miR-26a in hepatocyte proliferation during LR. We investigated the role of miR-26a as a pivotal regulator of hepatocyte proliferation in LR
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