Clément S Sobolewski C Gomes D Rojas A Goossens N Conzelmann S Calo N Negro F Foti M 2019 BACKGROUND & AIMS miR-21-5p is a potent oncogenic microRNA targeting many key tumour suppressors including phosphatase and tensin homolog (PTEN). We recently identified PTEN as a key factor modulated by hepatitis C virus (HCV) to promote virion egress. In hepatocytes, expression of HCV-3a core protein was sufficient to downregulate PTEN and to trigger lipid droplet accumulation. Here, we investigated whether HCV controls PTEN expression through miR-21-5p-dependent mechanisms to trigger steatosis in hepatocytes and to promote HCV life cycle. METHODS MiR-21-5p expression in HCV-infected patients was evaluated by transcriptome meta-analysis. HCV replication and viral particle production were investigated in Jc1-infected Huh-7 cells after miR-21-5p inhibition. PTEN expression and steatosis were assessed in HCV-3a core protein-expressing Huh-7 cells and in mouse primary hepatocytes having miR-21-5p inhibited or genetically deleted respectively. HCV-3a core-induced steatosis was assessed in vivo in Mir21a knockout mice. RESULTS MiR-21-5p expression was significantly increased in hepatic tissues from HCV-infected patients. Infection by HCV-Jc1, or transduction with HCV-3a core, upregulated miR-21-5p expression and/or activity in Huh-7 cells. miR-21-5p inhibition decreased HCV replication and release of infectious virions by Huh-7 cells. HCV-3a core-induced PTEN downregulation and steatosis were further prevented in Huh-7 cells following miR-21-5p inhibition or in Mir21a knockout mouse primary hepatocytes. Finally, steatosis induction by AAV8-mediated HCV-3a core expression was reduced in vivo in Mir21a knockout mice. CONCLUSION MiR-21-5p activation by HCV is a key molecular step, promoting both HCV life cycle and HCV-3a core-induced steatosis and may be among the molecular changes induced by HCV-3a to promote carcinogenesis. https://sonar.ch/global/documents/171795 eng info:eu-repo/semantics/altIdentifier/doi/10.1111/liv.14112 info:eu-repo/semantics/altIdentifier/pmid/30938910 Liver international : official journal of the International Association for the Study of the Liver. - 2019 hepatitis C lipid metabolism microRNA phosphatase and tensin homolog Animals Carcinogenesis Cell Line, Tumor Down-Regulation Fatty Liver Hepacivirus Hepatocytes Humans Lipid Metabolism Liver Mice Mice, Knockout MicroRNAs PTEN Phosphohydrolase Up-Regulation Viral Core Proteins Virus Replication Activation of the oncogenic miR-21-5p promotes HCV replication and steatosis induced by the viral core 3a protein. http://purl.org/coar/resource_type/c_6501