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Hepatitis B and Hepatitis C Virus Infection Promote Liver Fibrogenesis through a TGF-β1–Induced OCT4/Nanog Pathway
- Source :
- J Immunol
- Publication Year :
- 2022
- Publisher :
- The American Association of Immunologists, 2022.
-
Abstract
- Hepatitis B virus (HBV)/hepatitis C virus (HCV) coinfection accelerates liver fibrosis progression compared with HBV or HCV monoinfection. Octamer binding transcription factor 4 (OCT4) and Nanog are direct targets of the profibrogenic TGF-β1 signaling cascade. We leveraged a coculture model to monitor the effects of HBV and HCV coinfection on fibrogenesis in both sodium taurocholate cotransporting polypeptide–transfected Huh7.5.1 hepatoma cells and LX2 hepatic stellate cells (HSCs). We used CRISPR-Cas9 to knock out OCT4 and Nanog to evaluate their effects on HBV-, HCV-, or TGF-β1–induced liver fibrogenesis. HBV/HCV coinfection and HBx, HBV preS2, HCV Core, and HCV NS2/3 overexpression increased TGF-β1 mRNA levels in sodium taurocholate cotransporting polypeptide–Huh7.5.1 cells compared with controls. HBV/HCV coinfection further enhanced profibrogenic gene expression relative to HBV or HCV monoinfection. Coculture of HBV and HCV monoinfected or HBV/HCV coinfected hepatocytes with LX2 cells significantly increased profibrotic gene expression and LX2 cell invasion and migration. OCT4 and Nanog guide RNA independently suppressed HBV-, HCV-, HBV/HCV-, and TGF-β1–induced α-SMA, TIMP-1, and Col1A1 expression and reduced Huh7.5.1, LX2, primary hepatocyte, and primary human HSC migratory capacity. OCT4/Nanog protein expression also correlated positively with fibrosis stage in liver biopsies from patients with chronic HBV or HCV infection. In conclusion, HBV and HCV independently and cooperatively promote liver fibrogenesis through a TGF-β1–induced OCT4/Nanog-dependent pathway.
- Subjects :
- Adult
Liver Cirrhosis
Male
Hepatitis B virus
Immunology
Organic Anion Transporters, Sodium-Dependent
Hepacivirus
Article
Transforming Growth Factor beta1
Gene Knockout Techniques
Cell Movement
Cell Line, Tumor
Hepatic Stellate Cells
Humans
Immunology and Allergy
Tissue Inhibitor of Metalloproteinase-1
Symporters
Coinfection
Nanog Homeobox Protein
Hepatitis B
Hepatitis C
Actins
Collagen Type I, alpha 1 Chain
Liver
Hepatocytes
Female
CRISPR-Cas Systems
Octamer Transcription Factor-3
Subjects
Details
- ISSN :
- 15506606 and 00221767
- Volume :
- 208
- Database :
- OpenAIRE
- Journal :
- The Journal of Immunology
- Accession number :
- edsair.doi.dedup.....ae23c513075e9796ba5c96c9ef8cfcbf