title: Reduction of microRNA 122 expression in IFNL3 CT/TT carriers and during progression of fibrosis in patients with chronic hepatitis C.
abstract: The microRNA miR-122 is highly expressed in the liver and stimulates hepatitis C virus (HCV) replication in vitro. IFNL3 (lambda-3 interferon gene) polymorphisms and the expression of miR-122 have been associated with sustained virological response (SVR) to treatment with pegylated interferon plus ribavirin in patients with chronic hepatitis C (CHC). We investigated, in vivo, the relationship between miR-122 expression, IFNL3 polymorphism, fibrosis, and response to PEG-IFN plus ribavirin. Pretreatment liver biopsy specimens and serum samples from 133 patients with CHC were included. Sixty-six patients achieved SVR, and 64 failed to respond to the treatment (43 nonresponders [NR] and 21 relapsers [RR]). All stages of fibrosis were represented, with 39, 50, 23, and 19 patients, respectively, having Metavir scores of F1, F2, F3, and F4. miR-122 expression was assessed by real-time quantitative PCR (RT-qPCR) and IFNL3 rs12979860 by direct sequencing. Hepatic miR-122 expression was higher in patients with the IFNL3 CC genotype than in those with the IFNL3 CT or TT genotype, in all patients (P = 0.025), and in NRs plus RRs (P = 0.013). Increased hepatic miR-122 was more strongly associated with complete early virological response (cEVR) (P = 0.003) than with SVR (P = 0.016). In multivariate analysis, increased hepatic miR-122 was only associated with the IFNL3 CC genotype. miR-122 was decreased in patients with advanced fibrosis (Metavir scores of F3 and F4) compared to its levels in patients with mild and moderate fibrosis (F1 and F2) (P = 0.01). Serum and hepatic expression of miR-122 were not associated. The association between miR-122 and IFNL3 was stronger than the association between miR-122 and response to treatment. miR-122 may play a role in the early viral decline that is dependent on IFNL3 and the innate immune response.
  
  
  OBJECTIVE
  miR-122 plays a crucial role during HCV infection. Moreover, it was reported that miR-122 binding within the HCV genome stimulates its replication. Moreover, miR-122 is highly expressed within hepatocytes, where it regulates many cellular pathways. A reduction of miR-122 expression has been suggested to be associated with responsiveness to IFN-based therapy in patients with chronic hepatitis C. Several independent genome-wide association studies reported a strong association between IFNL3 polymorphism and responsiveness to IFN-based therapy. We report here a strong association between the expression of miR-122 and IFNL3 polymorphism that is independent of the response to the treatment. Our data suggest that modification of miR-122 expression may play an important role in the molecular mechanism associated with IFNL3 polymorphism. Moreover, we report a reduction of miR-122 at more advanced stages of fibrosis in patients with chronic hepatitis C.
authors.affiliation: INSERM, UMR1149, Team Physiopathology and Treatment of Viral Hepatitis, Centre de Recherche sur l'Inflammation, BP 416, Paris, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Estrabaud
authors.forename: Martine
authors.initials: M
authors.lastname: Lapalus
authors.forename: Philippe
authors.initials: P
authors.lastname: Broët
authors.forename: Kevin
authors.initials: K
authors.lastname: Appourchaux
authors.forename: Simon
authors.initials: S
authors.lastname: De Muynck
authors.forename: Olivier
authors.initials: O
authors.lastname: Lada
authors.forename: Michelle
authors.initials: M
authors.lastname: Martinot-Peignoux
authors.forename: Ivan
authors.initials: I
authors.lastname: Bièche
authors.forename: Dominique
authors.initials: D
authors.lastname: Valla
authors.forename: Pierre
authors.initials: P
authors.lastname: Bedossa
authors.forename: Patrick
authors.initials: P
authors.lastname: Marcellin
authors.forename: Michel
authors.initials: M
authors.lastname: Vidaud
authors.forename: Tarik
authors.initials: T
authors.lastname: Asselah
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D001219:Aspartate Aminotransferases / Q000097:blood; D004359:Drug Therapy, Combination; D005786:Gene Expression Regulation / Q000235:genetics*; D005838:Genotype; D019698:Hepatitis C, Chronic / Q000150:complications* / Q000188:drug therapy; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use; D007372:Interferons; D007378:Interleukins / Q000235:genetics*; D016014:Linear Models; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism*; D035683:MicroRNAs / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012254:Ribavirin / Q000627:therapeutic use; D018709:Statistics, Nonparametric; D019562:Viral Load; D000095022:Interferon Lambda
chemical_list: D000410:Alanine Transaminase; D001219:Aspartate Aminotransferases; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D035683:MicroRNAs; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012254:Ribavirin; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C531907:MIRN122 microRNA, human; C417083:peginterferon alfa-2b