Activation of the oncogenic miR‐21‐5p promotes HCV replication and steatosis induced by the viral core 3a protein

摘要

Abstract 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.