Acute liver injury upregulates microRNA-491-5p in mice, and its overexpression sensitizes Hep G2 cells for tumour necrosis factor-α-induced apoptosis

Abstract

Background: MicroRNAs (miRNAs) have emerged as novel genetic regulators of cell functions such as proliferation, apoptosis and cancer. Aims: The aim of this study was to evaluate the role of a specific miRNA in modulating hepatic cell functions. Methods: C57Bl/6 mice were administered anti-fas receptor antibodies to induce liver cell apoptosis. miRNAs were purified from the liver tissue and evaluated using an miRNA microarray. The role of miRNA-491_5p, which was overexpressed in the model, in modulating hepatic cell functions was evaluated. miRNA-491_5p was overexpressed in Hep G2 cells, followed by the addition of tumour necrosis factor (TNF)-α, and induction of apoptosis as well as genes involved in apoptosis pathways were evaluated. The effect of miRNA-491_5p target genes on apoptosis was also analysed by inhibiting their expression by siRNA-induced gene silencing. Results: Upregulation of miRNA-491_5p was found in a high-dose anti-fas receptor antibody group. Overexpression of microRNA-491_5p sensitized Hep G2 cells for TNF-α-induced apoptosis, and also caused an inhibition of α-fetoprotein, (AFP), heat shock protein-90 (hsp-90) and nuclear factor-κB (NF-κB). Overexpression of miRNA-491_5p or inhibition of AFP and hsp-90 resulted in an increased apoptosis in TNF-α-treated Hep G2 cells. Conclusions: One of the miRNAs that is associated with the acute liver injury mouse model, miRNA-491_5p, sensitizes Hep G2 cells for TNF-α-induced apoptosis, at least in part, by inhibiting AFP, hsp-90 and NF-κB. © 2009 John Wiley & Sons A/S.