Abstract and Introduction
Abstract
MicroRNAs (miRNAs) can be defined as small, noncoding sets of 19 to 24 nucleotides that have been associated with messenger RNA expression. miRNAs are members of a class of small regulatory RNAs that includes small interfering RNAs (siRNAs). miRNAs regulate the expression of downstream gene targets, including transcription factors, oncogenes, and tumor suppressor genes. Transcriptional profiling using genomic microarrays and beads has enabled the discovery of numerous miRNAs that are differentially expressed in normal tissues vs tumors and associated with cancer development, diagnosis, and prognosis. miRNA signatures can be used to detect and classify cancer and predict the severity of disease, with certain profiles of miRNA expression linked to aggressive cancers with advanced disease present at diagnosis. miRNAs have also become targets of novel anticancer gene therapy with antisense molecules that can inhibit miRNA activity currently being tested for their efficacy in a strategy of reducing miRNA activity on reporter genes bearing miRNA-binding sites. In the future, sophisticated genomic and proteomic techniques combined with complex bioinformatics data analyses will be required to translate these recent basic science discoveries to clinically useful diagnostic tests.
Introduction
MicroRNAs (miRNAs) are small, noncoding, single-stranded segments of RNA containing 19 to 24 nucleotides that have been associated with the regulation of messenger RNA (mRNA) expression. miRNAs reduce the transcription and translation of mRNA, thereby down-regulating gene expression. The genes that encode miRNAs are transcribed from DNA but not translated into protein. miRNAs are processed from primary transcripts known as pri-miRNA to form short stem-loop structures called pre-miRNA. The pri-miRNA is subsequently converted to functional miRNA (see "Biogenesis of miRNA"). Fully formed miRNAs are partially complementary to one or more mRNA molecules. miRNAs are a class of small regulatory RNAs that includes these miRNAs and the small interfering RNAs known as siRNAs. It is believed that there are as many as 1,000 miRNAs in the human genome and that up to 30% of human genes are regulated by miRNAs. For some human genes, more than 1 miRNA may be involved in their regulation. More than 80% of conserved miRNAs are tissue-specific. miRNAs silence their target mRNAs by a variety of mechanisms.
In 2002, Calin and coworkers for the first time reported that down-regulation or outright deletions of the miRNAs, miR-15a and miR-16-1, are associated with genomic instability at the 13q14 locus in most patients diagnosed with chronic lymphocytic leukemia. In the subsequent 5 years, a substantial number of studies and reviews have associated the presence of various miRNAs with cell proliferation, resistance to apoptosis, and differentiation in cancer cells. The miR-15a and miR-16-1 are localized to the intron of an uncharacterized noncoding RNA gene, deleted in lymphocytic leukemia 2 (DLEU2). Deletions of miRNA-regulated genes such as DLEU2 have been detected in more than 65% of chronic lymphocytic leukemia cases, in 50% of mantle-cell lymphomas, in 16% to 40% of multiple myelomas, and in 60% of prostate cancers. Other miRNA abnormalities have been reported in a wide variety of human neoplasms, including other hematologic malignancies such as promyelocytic leukemia; in benign tumors such as leiomyoma and pituitary adenoma; multiple types of carcinomas, including pancreatic, esophageal, thyroid, lung, and breast; and neuroblastomas and glioblastomas.