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

Authors: Choi, S. S.; Claridge, L. C.; Jhaveri, R.; Swiderska-Syn, M.; Clark, P.; Suzuki, A.; Pereira, T. A.; Mi, Z.; Kuo, P. C.; Guy, C. D.; Pereira, F. E.; Diehl, A. M.; Patel, K.; Syn, W. K.
Article Title: Osteopontin is up-regulated in chronic hepatitis C and is associated with cellular permissiveness for hepatitis C virus replication
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.
Keywords: Female; Humans; Male; Up-Regulation; Adult; Middle Aged; Real-Time Polymerase Chain Reaction; Surgery; Base Sequence; DNA Primers; Hepacivirus/physiology; Hepatitis C, Chronic/physiopathology; Osteopontin/blood/physiology; Reverse Transcriptase Polymerase Chain Reaction; Virus Replication
Journal Title: Clinical science (London, England : 1979)
Volume: 126
Issue: 12
ISSN: 1470-8736; 0143-5221
Publisher: Unknown  
Journal Place: England
Date Published: 2014
Start Page: 845
End Page: 855
Language: eng
Notes: LR: 20140613; GR: 5K08DK080980/DK/NIDDK NIH HHS/United States; GR: K08 DK080980/DK/NIDDK NIH HHS/United States; GR: R03DK084120/DK/NIDDK NIH HHS/United States; JID: 7905731; 0 (DNA Primers); 106441-73-0 (Osteopontin); NIHMS586297; OID: NLM: NIHMS586297 [Available on 06/01/15]; OID: NLM: PMC4055032 [Available on 06/01/15]; PMCR: 2015/06/01 00:00; ppublish