A microRNA-21 surge facilitates rapid cyclin D1 translation and cell cycle progression in mouse liver regeneration
Raymond Ng, Guisheng Song, Garrett R. Roll, Niels M. Frandsen, Holger Willenbring
Raymond Ng, Guisheng Song, Garrett R. Roll, Niels M. Frandsen, Holger Willenbring
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Research Article Hepatology

A microRNA-21 surge facilitates rapid cyclin D1 translation and cell cycle progression in mouse liver regeneration

Abstract

MicroRNA-21 (miR-21) is thought to be an oncomir because it promotes cancer cell proliferation, migration, and survival. miR-21 is also expressed in normal cells, but its physiological role is poorly understood. Recently, it has been found that miR-21 expression is rapidly induced in rodent hepatocytes during liver regeneration after two-thirds partial hepatectomy (2/3 PH). Here, we investigated the function of miR-21 in regenerating mouse hepatocytes by inhibiting it with an antisense oligonucleotide. To maintain normal hepatocyte viability and function, we antagonized the miR-21 surge induced by 2/3 PH while preserving baseline expression. We found that knockdown of miR-21 impaired progression of hepatocytes into S phase of the cell cycle, mainly through a decrease in levels of cyclin D1 protein, but not Ccnd1 mRNA. Mechanistically, we discovered that increased miR-21 expression facilitated cyclin D1 translation in the early phase of liver regeneration by relieving Akt1/mTOR complex 1 signaling (and thus eIF-4F–mediated translation initiation) from suppression by Rhob. Our findings reveal that miR-21 enables rapid hepatocyte proliferation during liver regeneration by accelerating cyclin D1 translation.

Authors

Raymond Ng, Guisheng Song, Garrett R. Roll, Niels M. Frandsen, Holger Willenbring

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Figure 1

miR-21–ASO injected into the tail vein facilitates inhibition of increased miR-21 expression and derepression of its target genes after 2/3 PH.

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miR-21–ASO injected into the tail vein facilitates inhibition of increas...
(A) Time course of miR-21 expression after 2/3 PH. miR-21 levels were determined by qRT-PCR. Arrows indicate time points of miR-21–ASO or carrier injection and liver analysis relative to 2/3 PH. Liver samples obtained by 2/3 PH (Analysis 0 hours after 2/3 PH) were used to define baseline levels in the quiescent liver. (B) qRT-PCR showed that miR-21–ASO injections at 6 or 10 hours after 2/3 PH were similarly effective in antagonizing the peak of the surge in miR-21 expression after 2/3 PH. (C) Repression of Btg2 mRNA levels in livers of control mice after 2/3 PH was reversed in mice injected with miR-21–ASO at 6 or 10 hours after 2/3 PH. At least 3 mice were analyzed for each time point and treatment. Control mice were injected with carrier. Data represent mean ± SEM. *P < 0.05.