MicroRNAs in Human Disease

The expanding inventory of human miRNAs along with their highly diverse expression patterns and high number of potential target mRNAs suggest that miRNAs are involved in a wide variety of human diseases. One is spinal muscular atrophy (SMA), a paediatric neurodegenerative disease caused by reduced protein levels or loss-of-function mutations of the survival of motor neurons (SMN) gene.116 A mutation in the target site of miR-189 in the human SLITRK1 gene was recently shown to be associated with Tourette's syn-drome,117 while another recent study reported that the hepatitis C virus (HCV) RNA genome interacts with a host-cell miRNA, the liver-specific miR-122a, to facilitate its replication in the host.118 Other diseases in which miRNAs or their processing machinery have been implicated include fragile X mental retardation (FXMR) caused by absence of the fragile X mental retardation protein (FMRP),119,120 DiGeorge syndrome,121 human immunodeficiency virus (HIV) replication and coronary artery disease. In addition, perturbed miRNA expression patterns have been reported in many human cancers. For example, the human miRNA genes miR15a and miR16-1 are deleted or downregulated in the majority of B-cell CLL cases, where a unique signature of 13 miRNA genes was shown to associate with prognosis and progression.124,125 The role of miRNAs in cancer is further supported by the fact that more than 50% of the human miRNA genes are located in cancer-associated genomic regions or at fragile sites.126 Systematic expression analysis of a diversity of human cancers revealed a general downregulation of miRNAs in tumours compared to normal tissues.127 Interestingly, miRNA-based classification of poorly differentiated tumours was successful, whereas mRNA profiles were highly inaccurate when applied to the same samples. miRNAs have also been shown to be deregulated in breast cancer,128 lung cancer129 and colon cancer,130 while the miR-17-92 cluster, which is amplified in human B-cell lymphomas, and miR-155, which is upregulated in Burkitt's lymphoma, have been identified as the first human miRNA oncogenes.131,132 Hence, disease-associated human miRNAs could represent a novel group of viable targets for therapeutic intervention.

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