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Liver Int. 2019 Apr 2. doi: 10.1111/liv.14112. [Epub ahead of print]

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

Author information

1
Division of Clinical Pathology, University Hospital, Geneva, Switzerland.
2
Faculty of Medicine, Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
3
Faculty of Medicine, Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
4
Division of Gastroenterology and Hepatology, University Hospital, Geneva, Switzerland.
5
Faculty of Medicine, Diabetes Center, University of Geneva, Geneva, Switzerland.

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.

KEYWORDS:

hepatitis C; lipid metabolism; microRNA; phosphatase and tensin homolog

PMID:
30938910
DOI:
10.1111/liv.14112

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