Kentaro Matsuura1,2,3, Valeria De Giorgi1, Cathy Schechterly1, Richard Y Wang1, Patrizia Farci4, Yasuhito Tanaka3, Harvey J Alter1. 1. Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD. 2. Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. 3. Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. 4. Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
Abstract
UNLABELLED: 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. CONCLUSION: 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).
UNLABELLED: 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 CHCpatients 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 CHCpatients, 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. CONCLUSION: 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: A J van der Meer; W R R Farid; M J Sonneveld; P E de Ruiter; A Boonstra; A J van Vuuren; J Verheij; B E Hansen; R J de Knegt; L J W van der Laan; H L A Janssen Journal: J Viral Hepat Date: 2012-08-27 Impact factor: 3.728
Authors: Etienne Patin; Zoltán Kutalik; Julien Guergnon; Stéphanie Bibert; Bertrand Nalpas; Emmanuelle Jouanguy; Mona Munteanu; Laurence Bousquet; Laurent Argiro; Philippe Halfon; Anne Boland; Beat Müllhaupt; David Semela; Jean-François Dufour; Markus H Heim; Darius Moradpour; Andreas Cerny; Raffaele Malinverni; Hans Hirsch; Gladys Martinetti; Vijayaprakash Suppiah; Graeme Stewart; David R Booth; Jacob George; Jean-Laurent Casanova; Christian Bréchot; Charles M Rice; Andrew H Talal; Ira M Jacobson; Marc Bourlière; Ioannis Theodorou; Thierry Poynard; Francesco Negro; Stanislas Pol; Pierre-Yves Bochud; Laurent Abel Journal: Gastroenterology Date: 2012-07-27 Impact factor: 22.682
Authors: Eoin P Brennan; Karen A Nolan; Emma Börgeson; Oisín S Gough; Caitríona M McEvoy; Neil G Docherty; Debra F Higgins; Madeline Murphy; Denise M Sadlier; Syed Tasadaque Ali-Shah; Patrick J Guiry; David A Savage; Alexander P Maxwell; Finian Martin; Catherine Godson Journal: J Am Soc Nephrol Date: 2013-03-21 Impact factor: 10.121
Authors: Hadi Valadi; Karin Ekström; Apostolos Bossios; Margareta Sjöstrand; James J Lee; Jan O Lötvall Journal: Nat Cell Biol Date: 2007-05-07 Impact factor: 28.824
Authors: Bo Wang; Jay C Jha; Shinji Hagiwara; Aaron D McClelland; Karin Jandeleit-Dahm; Merlin C Thomas; Mark E Cooper; Phillip Kantharidis Journal: Kidney Int Date: 2013-10-02 Impact factor: 10.612
Authors: Philipp Diehl; Alba Fricke; Laura Sander; Johannes Stamm; Nicole Bassler; Nay Htun; Mark Ziemann; Thomas Helbing; Assam El-Osta; Jeremy B M Jowett; Karlheinz Peter Journal: Cardiovasc Res Date: 2012-01-18 Impact factor: 10.787
Authors: Cody Orr; Rob Myers; Biao Li; Zhaoshi Jiang; John Flaherty; Anuj Gaggar; Eric G Meissner Journal: Liver Int Date: 2020-05-02 Impact factor: 5.828
Authors: Kyle S McCommis; Wesley T Hodges; Elizabeth M Brunt; Ilke Nalbantoglu; William G McDonald; Christopher Holley; Hideji Fujiwara; Jean E Schaffer; Jerry R Colca; Brian N Finck Journal: Hepatology Date: 2017-03-30 Impact factor: 17.425