Osteopontin is up-regulated in chronic hepatitis C and is associated with cellular permissiveness for hepatitis C virus replication

Choi, Steve S., Claridge, Lee C., Jhaveri, Ravi, Swiderska-Syn, Marzena, Clark, Paul, Suzuki, Ayako, Pereira, Thiago A., Mi, Zhiyong, Kuo, Paul C., Guy, Cynthia D., Pereira, Fausto E. L., Diehl, Anna Mae, Patel, Keyur and Syn, Wing-Kin (2014) Osteopontin is up-regulated in chronic hepatitis C and is associated with cellular permissiveness for hepatitis C virus replication. Clinical Science, 126 12: 845-855. doi:10.1042/CS20130473


Author Choi, Steve S.
Claridge, Lee C.
Jhaveri, Ravi
Swiderska-Syn, Marzena
Clark, Paul
Suzuki, Ayako
Pereira, Thiago A.
Mi, Zhiyong
Kuo, Paul C.
Guy, Cynthia D.
Pereira, Fausto E. L.
Diehl, Anna Mae
Patel, Keyur
Syn, Wing-Kin
Title Osteopontin is up-regulated in chronic hepatitis C and is associated with cellular permissiveness for hepatitis C virus replication
Journal name Clinical Science   Check publisher's open access policy
ISSN 0143-5221
1470-8736
Publication date 2014-06-01
Year available 2014
Sub-type Article (original research)
DOI 10.1042/CS20130473
Volume 126
Issue 12
Start page 845
End page 855
Total pages 11
Place of publication London United Kingdom
Publisher Portland Press
Collection year 2015
Abstract OPN (osteopontin)) is a Hh (Hedgehog)-regulated cytokine that is up-regulated during chronic liver injury and directly promotes fibrosis. We have reported that Hh signalling enhances viral permissiveness and replication in HCV (hepatitis C virus)-infected cells. Hence we hypothesized that OPN directly promotes HCV replication, and that targeting OPN could be beneficial in HCV. In the present study, we compared the expression of OPN mRNA and protein in HCV (JFH1)-infected Huh7 and Huh7.5 cells, and evaluated whether modulating OPN levels using exogenous OPN ligands (up-regulate OPN) or OPN-specific RNA-aptamers (neutralize OPN) leads to changes in HCV expression. Sera and livers from patients with chronic HCV were analysed to determine whether OPN levels were associated with disease severity or response to therapy. Compared with Huh7 cells, Huh7.5 cells support higher levels of HCV replication (15-fold) and expressed significantly more OPN mRNA (30-fold) and protein. Treating Huh7 cells with OPN ligands led to a dose-related increase in HCV (15-fold) and OPN (8-fold) mRNA. Conversely, treating Huh7.5 cells with OPN-specific RNA aptamers inhibited HCV RNA and protein by >50% and repressed OPN mRNA to basal levels. Liver OPN expression was significantly higher (3-fold) in patients with advanced fibrosis. Serum OPN positively correlated with fibrosis-stage (P=0.009), but negatively correlated with ETBCR (end-of-treatment biochemical response), ETVR (end-of-treatment virological response), SBCR (sustained biochemical response) and SVR (sustained virological response) (P=0.007). The OPN fibrosis score (serum OPN and presence of fibrosis ≥F2) may be a predictor of SVR. In conclusion, OPN is up-regulated in the liver and serum of patients with chronic hepatitis C, and supports increased viral replication. OPN neutralization may be a novel therapeutic strategy in chronic hepatitis C. © The Authors Journal compilation.
Keyword Fibrosis
Hedgehog
Hepatitis
Osteopontin
Replication
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
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Created: Thu, 17 Jul 2014, 19:10:10 EST by Anthony Yeates on behalf of School of Medicine