MIRNAS SIGNATURES FOR DEVELOPING PRECISE BIOMARKERS FOR HBV-ASSOCIATED LIVER DISEASES AND IN DEVELOPMENT

摘要

Hepatitis B virus (HBV) can manipulate the miRNA regulatory networks in infected cells to create a permissive environment for viral replication, cellular injury, disease onset and its progression. Understanding miRNA expression in liver of HBV-infected subjects could unravel pathogenic mechanisms. We investigated differentially expressed miRNAs by microarray and real time PCR in the liver biopsy and serum samples from different stages of HBV associated liver diseases (immune tolerant, acute viral hepatitis, no fibrosis, early fibrosis (F1+F2), late fibrosis (F3+F4) and healthy controls). The miRNA expression levels were determined by unsupervised hierarchical clustering and principal component analyses. Analysis of miRNA-mRNA regulatory network clearly showed 17 miRNAs and 18 target gene interactions with four distinct nodes each representing a stage-specific gene regulation by miRNAs during Hepatitis B-related disease progression. The IT group showed elevated levels of miR-199a-5p, miR-221-3p and Let-7a-3p which can target host genes involved in innate immune response and viral replication. In AVH group, miR-125b-5p and miR-3613-3p were upregulated whereas miR-940 was down-regulated which could influence cell proliferation via STAT3. In early fibrosis, miR-34tH3p, miR-1224- 3p and miR-1227- 3p were up while miR-499a-5p was down which together could mediate chronic inflammation. In advanced fibrosis, miR-1, miR-10b-5p, miR-96-5p, miR-133b and miR-671-5p were up while miR-20b-5p and miR-455-3p were down and are associated with chronic disease process. Interestingly, only 8 of 17 liver specific miRNAs exhibited a similar expression pattern in patient sera possibly due to their altered secretion from liver, stability or uptake by other target cells. Molecular signatures identified in this study provide deeper understanding of HBVassociated liver diseases and may be helpful in developing early stage disease diagnostics and targeted novel therapeutics.