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. 2014 Jun;88(11):6394-402.
doi: 10.1128/JVI.00016-14. Epub 2014 Mar 26.

Reduction of microRNA 122 expression in IFNL3 CT/TT carriers and during progression of fibrosis in patients with chronic hepatitis C

Emilie Estrabaud  1 , Martine Lapalus, Philippe Broët, Kevin Appourchaux, Simon De Muynck, Olivier Lada, Michelle Martinot-Peignoux, Ivan Bièche, Dominique Valla, Pierre Bedossa, Patrick Marcellin, Michel Vidaud, Tarik Asselah
Affiliations

Reduction of microRNA 122 expression in IFNL3 CT/TT carriers and during progression of fibrosis in patients with chronic hepatitis C

Emilie Estrabaud et al. J Virol. 2014 Jun.

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.

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Figures

FIG 1
FIG 1
The hepatic expression of miR-122 is associated with early virological response. The expression of miR-122 was assessed by RT-qPCR. The ΔCp (ΔCpt = 2ΔCpsample) of miR-122 was calculated and normalized to the ΔCp value of SNORD44 in each biopsy specimen. The histograms represent the mean log expression of miR-122/SNORD44 within the groups of patients, comprising those with sustained virological response (SVR), nonresponse or relapse (NR/RR), primary nonresponse (pNR), and complete early virological response (cEVR), normalized to the expression of miR-122 within the group of histologically normal liver biopsy specimens. (A) The hepatic expression of miR-122 was compared in patients with pNR and cEVR. (B) The hepatic expression of miR-122 was compared in patients with NR/RR and SVR. The nonparametric Wilcoxon Mann-Whitney test was used to compare miR-122 expression. The numbers in parentheses show the number of patients in each group.
FIG 2
FIG 2
The IFNL3 CC genotype is associated with accumulation of hepatic miR-122. The expression of miR-122 was assessed by RT-qPCR. The ΔCp (ΔCpt = 2ΔCpsample) of miR-122 was calculated and normalized to the ΔCp value of SNORD44 in each biopsy specimen. (A to D) The histograms represent the mean log expression of miR-122/SNORD44 for all patients (A), patients who failed to respond to the treatment (NR/RR) (B), and SVR patients (C). The boxes and whiskers are as described in the legend to Fig. 1. We used the nonparametric Wilcoxon Mann-Whitney test to compare the expression of miR-122 in IFNL3 CC and CT/TT patients. (D) Reduction of hepatic expression of miR-122 in IFNL3 CT/TT patients who failed to respond to the treatment. The histograms represent the mean expression of miR-122/SNORD44 in IFNL3 CC and CT/TT patients with either SVR or NR/RR, normalized to the expression of miR-122 within the group of histologically normal liver biopsy specimens. The errors bars represent the standard deviations. The numbers in parentheses show the number of patients within each group.
FIG 3
FIG 3
Modification of hepatic miR-122 expression at different stages of fibrosis in chronic hepatitis C. The expression of miR-122 was assessed by RT-qPCR. The ΔCp (ΔCpt = 2ΔCpsample) of miR-122 was calculated and normalized to the ΔCp value of SNORD44. (A and B) The histograms represent the mean expression of miR-122/SNORD44 within the groups of patients at different stages of fibrosis (F1 to F4). Modification of miR-122 expression at the different stages of fibrosis is shown for all patients with any HCV genotype (A) and for HCV genotype 1 patients only (B). The expression of mir-122 was compared in F1–F2 versus F3–F4 and in F1 versus F2–F4 in patients with all genotypes (A) and only genotype 1 (B). The number above the brackets is the P value for each association. We performed the nonparametric Wilcoxon Mann-Whitney test to compare miR-122 in each group of patients, including those with histologically normal liver biopsy samples (N) and those with stage F1 to F4 fibrosis. The numbers in parentheses show the number of patients within each group. The errors bars represent the standard deviations. (C) Reduction of miR-122 expression during early fibrosis progression. Five patients received 2 liver biopsies at different stages of fibrosis (x axis). The paired samples were obtained at intervals varying from 2 years and 5 months to 8 years and 7 months. The number next to each line is the identification number for each patient, also used in Table S1 in the supplemental material.
FIG 4
FIG 4
Lack of association between hepatic and serum miR-122. Log expression of hepatic and serum miR-122 was compared in patients with CHC. We tested the null hypothesis that the Pearson product moment correlation coefficient is zero using the classical statistical test which follows Student's t distribution.
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