Reduction of MicroRNA 122 Expression in
IFNL3
CT/TT Carriers and during Progression of Fibrosis in Patients with Chronic Hepatitis C
Authors: Estrabaud Emilie , Lapalus Martine , Broët Philippe , Appourchaux Kevin , Muynck Simon De , Lada Olivier , Martinot-Peignoux Michelle , Bièche Ivan , Valla Dominique , Bedossa Pierre , Marcellin Patrick , Vidaud Michel , Asselah Tarik 
Published: March 2014

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.

IMPORTANCE
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.