Journal article
Activation of the oncogenic miR-21-5p promotes HCV replication and steatosis induced by the viral core 3a protein.
- Clément S Division of Clinical Pathology, University Hospital, Geneva, Switzerland.
- Sobolewski C Faculty of Medicine, Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
- Gomes D Faculty of Medicine, Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
- Rojas A Faculty of Medicine, Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
- Goossens N Division of Gastroenterology and Hepatology, University Hospital, Geneva, Switzerland.
- Conzelmann S Faculty of Medicine, Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
- Calo N Faculty of Medicine, Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
- Negro F Division of Clinical Pathology, University Hospital, Geneva, Switzerland.
- Foti M Faculty of Medicine, Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
- 2019-04-03
Published in:
- 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
English
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.
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.
- Language
-
- English
- Open access status
- closed
- Identifiers
-
- DOI 10.1111/liv.14112
- PMID 30938910
- Persistent URL
- https://sonar.ch/global/documents/171795
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