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Can microRNAs put the brakes on cancer?

Yale Medicine Magazine, 2006 - Autumn


Between 20 and 25 genetic letters long, microRNAs regulate the expression of genes involved in development.

One of the basic premises of biology is that our genetic code lies in our DNA, which, in turn, relies on RNA to transmit that code to build the proteins that carry out the chemical activities necessary for life.

In the early 1990s, however, scientists at Harvard Medical School discovered a genetic switch in the microscopic roundworm C. elegans that called into question long-held beliefs about the role of RNA. Lin-4 was the first of what would become known as microRNAs.

Only 22 genetic letters long, lin-4 is far shorter than a typical 1,000-letter RNA message, and rather than helping to build proteins, it sticks to messenger RNA and shuts down the expression of genes involved in early development.

It would be seven years before Frank Slack, Ph.D., showed thatlin-4 was no fluke. In 2000, while a postdoctoral fellow at Harvard, Slack, now associate professor of molecular, cellular and developmental biology at Yale, identified a second microRNA, let-7, that also governs development in C. elegans.

Then the floodgates opened. In the past five years, hundreds of gene-silencing microRNAs have been found in plants and animals, including over 200 in humans that may regulate more than a third of our genes. Because half of the C. elegansgenome matches our own, including the genes for let-7, Slack’s research is having an impact on our understanding of human development, aging and illness, especially cancer.

According to Slack, one of the primary roles of microRNAs is to put a brake on cell proliferation during development. “Initially in the human embryo, you’ve got cells just dividing, dividing, dividing—to make as many cells as possible,” he said. “But at some point you want to make an organ. MicroRNAs come on to tell cells to stop dividing and to start differentiating into organs. And they stay on all through life, to keep the cells from dividing again.” Slack believes that the uncontrolled cell division that is a hallmark of cancer might be caused when the check on cell growth imposed by microRNAs is somehow lifted. “In various cancers we’ve looked at, microRNAs have been shut off,” he said. “We think that causes cells to re-enter their cell division program and behave like they’re in the embryo.”

In particular, Slack has found that let-7 is tamped down in human tumors, unleashing Ras, a cell-proliferation gene that has long been implicated in cancers of the lung and pancreas.

Slack is collaborating with Joanne B. Weidhaas, M.D., Ph.D., assistant professor of therapeutic radiology, to develop microRNA-based diagnostic tools and treatments. According to Weidhaas, genomic analyses of tumors and cancer therapies targeting single genes have been largely disappointing, because hundreds of genes are faulty in any given cancer and it has been difficult to discern which mutations are most important. The excitement surrounding microRNAs, she said, stems from their ability to regulate entire suites of genes that underlie biological pathways.

A 2005 study published in the journal Nature found that measuring the levels of just 217 microRNAs could generate clearer genetic signatures for tumors than 16,000 probes for messenger RNA. Encouraged by these results, Slack and Weidhaas hope within two years to perfect a microRNA-based screening device that could help tailor cancer treatments to patients’ tumor types, and they are in the early stages of testing a let-7 inhalant therapy to rein in uncontrolled cell growth in lung cancer. In addition, Weidhaas has shown that raising let-7 levels in C. elegans makes the worm’s cells more sensitive to radiation, leading her to conclude that a let-7 treatment could be a powerful adjunct to standard radiotherapy.