MicroRNA signatures in liver diseases

Abstract

MicroRNAs (miRNAs) are an emerging class of highly conserved non-coding small RNAs that regulate gene expression at the post-transcriptional level. It is now clear that miRNAs can potentially regulate every aspect of cellular activity, including differentiation and development, metabolism, proliferation, apoptotic cell death, viral infection and tumorigenesis. Recent studies provide clear evidence that miRNAs are abundant in the liver and modulate a diverse spectrum of liver functions. Deregulation of miRNA expression may be a key pathogenetic factor in many liver diseases including viral hepatitis, hepatocellular cancer and polycystic liver diseases. A clearer understanding of the mechanisms involved in miRNA deregulation will offer new diagnostic and therapeutic strategies to treat liver diseases. Moreover, better understanding of miRNA regulation and identification of tissue-specific miRNA targets employing transgenic/knockout models and/or modulating oligonucleotides will improve our knowledge of liver physiology and diseases.

Figure 1

miRNA biogenesis and function in animal cells. Animal genomes have specific genes that encode miRNAs. Primary miRNA transcripts (pri-miRNAs) are processed into precursor miRNA (pre-miRNAs) stem-loops of approximately 60 nucleotides in length by the nuclear RNase III enzyme Drosha. These pre-miRNAs are transported to the cytoplasm via exportin-5 and are further processed by the ribonuclease Dicer. Mature miRNAs are then incorporated in the RNA-induced silencing complex (RISC) and interfere with the regulation of mRNA translation by targeting mRNAs resulting in mRNA degradation or translational repression.

Figure 2

Prediction of targets by miRNAs in the liver. The miRNAs are ordered by RR values (upper-axis). The higher values reflect lower expression of predicted target genes and are, therefore, indicative of miRNA activity. The numbers of genes predicted to be targeted by each miRNA (lower-axis) are indicated by the grey line. This figure is reprinted from Arora and Simpson[28] with the permission of the authors and the publisher.

Figure 3

Model of miR15a function in hepatic cystogenesis. A: In normal cholangiocytes, ciliary signaling activates intracellular signaling pathways resulting in miR15a expression and CDC25A repression. Decreased levels of CDC25A then lead to G1 arrest, preventing cyst formation; B: In cholangiocytes of polycystic liver, miR15a level is reduced as a result of mutation of molecules important to the ciliary signaling. Reduction of miR15a results in elevated Cdc25A level, increased cell proliferation, and cyst growth. This figure is reprinted from Chu and Friedman[49] with the permission of the authors and the publisher.