Correlation between microRNA expression levels and clinical parameters associated with chronic hepatitis C viral infection in humans

Abstract

MicroRNAs (miRNAs) are small RNAs that regulate gene expression pathways. Previous studies have shown interactions between hepatitis C virus (HCV) and host miRNAs. We measured miR-122 and miR-21 levels in HCV-infected human liver biopsies relative to uninfected human livers and correlated these with clinical patient data. miR-122 is required for HCV replication in vitro, and miR-21 is involved in cellular proliferation and tumorigenesis. We found that miR-21 expression correlated with viral load, fibrosis and serum liver transaminase levels. miR-122 expression inversely correlated with fibrosis, liver transaminase levels and patient age. miR-21 was induced Btwofold, and miR-122 was downregulated on infection of cultured cells with the HCV J6/JFH infectious clone, thus establishing a link to HCV. To further examine the relationship between fibrosis and the levels of miR-21 and miR-122, we measured their expression levels in a mouse carbon tetrachloride fibrosis model. As in the HCV-infected patient samples, fibrotic stage positively correlated with miR-21 and negatively correlated with miR-122 levels. Transforming growth factor b (TGF-b) is a critical mediator of fibrogenesis. We identified SMAD7 as a novel miR-21 target. SMAD7 is a negative regulator of TGF-b signaling, and its expression is induced by TGF-b. To confirm the relationship between miR-21 and the TGF-b signaling pathway, we measured the effect of miR-21 on a TGF-b-responsive reporter. We found that miR-21 enhanced TGF-b signaling, further supporting a relationship between miR-21 and fibrosis. We suggest a model in which miR-21 targeting of SMAD7 could increase TGF-b signaling, leading to increased fibrogenesis.

HepatomiRNoma: The proposal of a new network of targets for diagnosis, prognosis and therapy in hepatocellular carcinoma

“…This miRNA is the first to be studied as a therapeutic tool and other two studies (Connolly et al, 2008;Zhu et al, 2011) have shown that the transfection of tumor cells with antisense oligonucleotides specific for mir-21 leads to a reduction of the cell growth and survival. Likewise studies by Xu et al (2011a), Bihrer et al (2011), Marquez et al (2010 have shown that serum levels of miR-21 are increased with a progressive course from chronic hepatitis to cirrhosis and hepatocellular carcinoma. Multivariate analyses demonstrate that the only parameters to be associated with this miRNA are histological necroinflammation and viral load.…”

The Autoregulatory Feedback Loop of MicroRNA-21/Programmed Cell Death Protein 4/Activation Protein-1 (MiR-21/PDCD4/AP-1) as a Driving Force for Hepatic Fibrosis Development

“…4, C and D). Smad6/7 exhibits antagonistic effects on Smad2/3 phosphorylation (22) and is a direct target of miR-21 (4,5). Antagomir-21 increased Smad7 levels, whereas pre-miR-21 decreased Smad7 expression in both HSC-T6 cells and primary HSCs (Fig.…”

“…1F). 4 -treated Mice-To further confirm that miR-21 participated in and promoted the progression of hepatic fibrosis, chemically synthesized antagomirs were administered to knock down miR-21 expression. The miR-21 levels were determined in isolated HSCs from mice after antagomir-21/antago-ctrl treatment.…”

MicroRNAs in Liver Disease: Bench to Bedside

“…MiR-21 has been shown to regulate pro-and antiinflammatory cytokines and has been implicated in the development of fibrosis leading to chronic rejection following liver transplantation. 75,151 This has been also validated in an independent set of HCV+ LT recipients and demonstrated organ specificity (molecular pathways involved in liver injury, malignancy and hepatic disease), and relationship with immune response (T cell lineages development). 150 Farid et al have shown that circulating miR-122, miR-148, miR-194 are sensitive biomarkers for hepatocyte injury and rejection after liver transplantation.…”

“…74 Recently, Marquez et al analyzed the expression of miR-122 and miR-21 in liver biopsy samples of HCV-infected patients and uninfected controls and found miR-122 levels to be inversely correlated with fibrotic stage, ALT, AST, while miR-21 correlated positively. 75 It was speculated that the dysregulation of miR-21 and miR-122 rather than the expression levels, could be related to fibrosis.…”