title: Circulating let-7 levels in plasma and extracellular vesicles correlate with hepatic fibrosis progression in chronic hepatitis C.
abstract: The goal of this study was to determine whether an association exists between circulating microRNA (miRNA) levels and disease progression in chronic hepatitis C (CHC), whether plasma or extracellular vesicles (EVs) were optimal for miRNA measurement and their correlation with hepatic miRNA expression, and the mechanistic plausibility of this association. We studied 130 CHC patients prospectively followed over several decades. A comprehensive miRNA profile in plasma using microarray with 2578 probe sets showed 323 miRNAs differentially expressed between healthy individuals and CHC patients, but only six that distinguished patients with mild versus severe chronic hepatitis. Eventually, let-7a/7c/7d-5p and miR-122-5p were identified as candidate predictors of disease progression. Cross-sectional analyses at the time of initial liver biopsy showed that reduced levels of let-7a/7c/7d-5p (let-7s) in plasma were correlated with advanced histological hepatic fibrosis stage and other fibrotic markers, whereas miR-122-5p levels in plasma were positively correlated with inflammatory activity, but not fibrosis. Measuring let-7s levels in EVs was not superior to intact plasma for discriminating significant hepatic fibrosis. Longitudinal analyses in 60 patients with paired liver biopsies showed that let-7s levels in plasma markedly declined over time in parallel with fibrosis progression. However, circulating let-7s levels did not parallel those in the liver.
  
  
  
  Of all miRNAs screened, the let-7 family showed the best correlation with hepatic fibrosis in CHC. A single determination of let-7s levels in plasma did not have superior predictive value for significant hepatic fibrosis compared with that of fibrosis-4 index, but the rate of let-7s decline in paired longitudinal samples correlated well with fibrosis progression. Pathway analysis suggested that low levels of let-7 may influence hepatic fibrogenesis through activation of transforming growth factor β signaling in hepatic stellate cells. (Hepatology 2016;64:732-745).
authors.affiliation: Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD.|Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.|Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Matsuura
authors.affiliation: Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD.
authors.forename: Valeria
authors.initials: V
authors.lastname: De Giorgi
authors.affiliation: Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD.
authors.forename: Cathy
authors.initials: C
authors.lastname: Schechterly
authors.affiliation: Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD.
authors.forename: Richard Y
authors.initials: RY
authors.lastname: Wang
authors.affiliation: Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Farci
authors.affiliation: Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD.
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Alter
mesh_terms: D000328:Adult; D015331:Cohort Studies; D018450:Disease Progression; D000067128:Extracellular Vesicles / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D019698:Hepatitis C, Chronic / Q000097:blood* / Q000150:complications; D006801:Humans; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000097:blood* / Q000473:pathology / Q000821:virology; D008297:Male; D035683:MicroRNAs / Q000097:blood*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D035683:MicroRNAs; C487931:mirnlet7 microRNA, human