Dysregulation of microRNAs in human malignancy

Introduction Over the past twenty years, cancer geneticists have uncovered many of the genes responsible for the initiation and progression of the multi-step process of tumorigenesis (Vogelstein and Kinzler, 2004). Much of this research has focused on traditional protein-coding genes including oncogenes, tumor suppressors, and genes that maintain genome stability. Within the past five years, a new class of small non-coding RNAs called microRNAs (miRNAs or miRs) has been identified and recent evidence suggests that dysregulation of miRNAs is linked to the development of cancer. In 1993, the Ambros and Ruvkun laboratories discovered that a 21-nucleotide RNA molecule called lin-4 regulated the translation of a target message, lin-14, by base-pairing to its 3' untranslated region (Lee et al., 1993; Wightman et al., 1993). Subsequent work in this direction prompted the construction and sequencing of libraries of cloned small RNAs by several groups of investigators. Coupled with bioinformatic analyses of genomic sequence, these efforts led to the identification of several hundred miRNAs in Drosophila, C. elegans, and mammals (Lagos-Quintana et al., 2001; Lau et al., 2001; Lee and Ambros, 2001). More than 450 miRNAs have been identified in humans and recent estimates suggest there may be as many as 1000 (Bentwich et al., 2005: Berezikov et al., 2005). The biogenesis and function of microRNAs are detailed in various chapters in Part II of this book. In general, the analysis of many more miRNA-target interactions is required to better understand the mechanisms through which miRNAs elicit various effects.