YALE JOURNAL OF BIOLOGY AND MEDICINE 79 (2006), pp.131-140. Copyright © 2006. CANCER MECHANISMS The Role of MicroRNAs in Cancer Carlos E. Stahlhut Espinosa and Frank J. Slack* Department of Molecular, Cellular, and Developmental Biology, Yale University School of Medicine, New Haven, Connecticut Cancer is a complex and dynamic disease, involving a variety of changes in gene expression and structure. Traditionally, the study of cancer has focused on protein-coding genes, con- sidering these as the principal effectors and regulators of tumorigenesis. Recent advances, however, have brought non-protein-coding RNA into the spotlight. MicroRNAs (miRNAs)†, one such class of non-coding RNAs, have been implicated in the regulation of cell growth, differentiation, and apoptosis [1]. While their study is still at an early stage, and their mech- anism of action along with their importance in cancer is not yet fully understood, they may provide an important layer of genetic regulation in tumorigenesis, and ultimately become valuable therapeutic tools. INTRODUCTION MicroRNAs are small, non-coding RNAs of 18 to 24 nucleotides, discovered in 1993 in the nematode Caenorhabditis el- egans. Lee et al. [2] found that a gene cru- cial for C. elegans post-embryonic development, lin-4, does not code for a pro- tein, but rather is transcribed into a 22-nu- cleotide RNA molecule. This molecule could repress the expression of the lin-14 mRNA by directly interacting with its 3’ untranslated region (UTR) [3]. While this was recognized as a new method of gene regulation, it was initially considered as an oddity peculiar to C. elegans. The discov- ery of let-7, another small RNA involved in developmental timing in C. elegans [4], and the finding that both its sequence and temporal expression pattern were largely conserved in a variety of organisms [5] im- mediately suggested these small RNAs might in fact play important and conserved roles in gene regulation, and the identifica- tion of hundreds of miRNAs in the worm, fly, and mammalian genomes followed [1]. To date, more than 300 miRNAs have been discovered in humans, and computa- tional analyses predict that up to 1,000 miRNAs exist in the genome [6,7]. Since miRNAs can regulate more than one target, estimates indicate they may be able to reg- ulate up to 30 percent of the protein-coding genes in the human genome [8], highlight- ing their importance as global regulators of gene expression. miRNA BIOGENESIS AND METHOD OF ACTION MiRNAs are transcribed by RNA Polymerase II into large precursor RNAs, often several kilobases in length, called pri- *To whom all correspondence should be addressed: Carlos E. Stahlhut Espinosa and Frank J. Slack, Department of Molecular, Cellular, and Developmental Biology, Yale University School of Medicine, 266 Whitney Avenue, New Haven, CT 06520. Tel: 203-432-3493; E- mail: carlos.stahlhut@yale.edu; frank.slack@yale.edu. †Abbreviations: miRNAs, MicroRNAs; mRNA, Messenger Ribonucleic Acid. 131