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.

Analyzing the effect of MicroRNAs on Hepatogenic differentiation of Mesenchymal stem cells

“…Their data indicate thatmiR-21 overexpression in primary hepatocytes increased Akt expression levels and activation (p-Akt); equally, low miR-21 expression decreased Akt expression and activation, and PTEN mRNA and protein levels were up-or down regulated, separately, suggesting that miR-21 promoted PI3K/Akt activation in a PTEN-dependent manner in primary hepatocytes in vitro. These email facts are on the other hand to the findings of Ng et al (2012) who suggested that PTEN accumulation didn't inhibit Akt1 activation in liver regeneration.…”

“…Already more than 1000 human miRNA (Song et al, 2010). Ng et al (2012) from exactly the same group further focused on the role of miR-21 in mouse liver regeneration. They proposed a miR-21 dependent mechanism for translation of cyclin D1 in early phase of liver regeneration.…”

“…Although their researches primarily address the mechanisms behind themiR-21modulated cyclin D1 translation during liver regeneration, these results further boost the attractiveness of utilizing miR-21 as a possible tool in hepatic tissue engineering, e.g. by transitional up regulation for induction of hepatocyte proliferation (Ng et al, 2012). In a recently published study by Yan et al (2014) further evidence was as long as miR-21 accelerates hepatocyte proliferation.…”

Exosomes Derived from Hypoxic Oral Squamous Cell Carcinoma Cells Deliver miR-21 to Normoxic Cells to Elicit a Prometastatic Phenotype

“…Using miR-21 as an example, we showed that both cellular and exosomal miR-21 levels were significantly increased under hypoxia, suggesting that exosomal miRNA may at least partially reflect cellular miRNA profiles. miR-21 shows features of oncomirs by targeting many tumor suppressor genes related to cell proliferation, apoptosis, and invasion in multiple histologic types of cancer, including OSCC (42,43). Recently, studies have demonstrated that hypoxia induces miR-21 expression in a HIF-1a-dependent manner in pancreatic cancer cells (44) and cardiomyocytes (36).…”

Pluronic-based micelle encapsulation potentiates myricetin-induced cytotoxicity in human glioblastoma cells

“…41 MiR-21 is a negative regulator of p53 signaling and stimulates the expression of the cell cycle promoter cyclin D1. 22,43 It also induces tumor angiogenesis through targeting PTEN, leading to activated AKT and ERK1/2 signaling. 44 In the present study, DBTRG cells treated with miR-21 inhibitors showed significant reduction of EGFR, phosphorylated Akt (Ser 473), K-Ras, and Raf-1 ( Figure 7A and B).…”