Three papers published this past June —the result of collaborations involving several HHMI investigators—show explicit links between tiny RNA molecules and cancer.

These studies “change the landscape of cancer genetics,” according to Paul S. Meltzer, of the National Human Genome Research Institute at the National Institutes of Health, in an editorial in the June 9, 2005, issue of Nature, where the work was published.

One study, by HHMI investigators Todd R. Golub, H. Robert Horvitz, and Tyler Jacks, with colleagues, showed the potential of so-called microRNAs (miRNAs) as a powerful diagnostic tool for cancer. The second study, which involved a collaboration between HHMI investigator Scott W. Lowe and colleagues Gregory J. Hannon (recently selected to become an HHMI investigator) and Scott M. Hammond, established that a group of seven miRNAs—all produced from a single gene and then processed into discrete RNA segments—act similarly to a cancer-causing gene. The third study, by Joshua T. Mendell at the Johns Hopkins University School of Medicine, linked the expression of a common oncogene, myc, to that of six miRNAs.

		View Image MICRORNA PRODUCTION The precursor of an miRNA (pri-miRNA) is transcribed in the nucleus. It forms a stem_loop structure that is processed to form another precursor (pre-miRNA) before being exported to the cytoplasm. Further processing by the Dicer protein creates the mature miRNA, one strand of which is incorporated into the RNA-induced silencing complex (RISC). Base pairing between the miRNA and its target directs RISC to either destroy the mRNA or impede its translation into protein. The initial stem_loop configuration of the primary transcript provides structural clues that have been used to guide searches of genomic sequence for candidate miRNA genes. Image: Reprinted Courtesy of Nature, vol.435, pp. 745 to 748. ©2005 NPG

MicroRNAs are tiny molecules—about 22 nucleotides long—that regulate the expression of genes. They don't produce proteins, but they control the RNAs that do and thus are key players in many physiological and developmental processes. Discovered a little more than a decade ago, miRNAs have rapidly become the focus of considerable scientific scrutiny. But exactly what they do and how they work remain somewhat mysterious. So how did these puzzling gene regulators move onto center stage in such a short time? What made these scientists go after them as a cancer suspect?

“I believed, as early as 1980, that what the genes that later proved to encode miRNAs were doing biologically could be related to human cancer,” Horvitz recalls. Two genes, lin-4 and let-7, later discovered to encode miRNAs were first studied in Horvitz's lab at MIT—long before the term miRNA was even coined. The genes were found to regulate the timing of larval development in the roundworm Caenorhabditis elegans.

When these genes are mutated or eliminated, the timing and sequence of developmental events go awry. Mutations in lin-4, for example, cause certain cells in C. elegans to behave like cells of the same lineage at an earlier stage of development. When the function of lin-4 is lost, cells begin dividing as they would have at an earlier stage. Because abnormal cell proliferation is a hallmark of cancers, it seemed possible that genes like lin-4 might be linked to the malignant state.

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