MicroRNA Helps Suppress Tumors

The first microRNA was discovered in 1993, in worms. Many microRNAs now have been found in diverse plants and animals, including hundreds in humans. Moreover, microRNAs found in mammals regulate over one-third of the human genome, as shown in a 2005 study by the lab of Whitehead member Dr. David Bartel and colleagues. However, given the vast quantity of microRNAs, and the ability of individual microRNAs to target hundreds of genes, researchers have struggled to show the biologic impact of a specific microRNA on a specific target in mammals (although such connections have been shown in plants, worms and flies). Several groups have demonstrated that overexpression or underexpression of microRNA can play a role in certain tumors, but have not clarified the genes responsible.

Looking to find a promising target for an individual microRNA, Dr. Christine Mayr, a postdoctoral researcher in the Bartel lab, chose Hmga2, a gene that is defective in a wide range of tumors. In these tumors, the protein-producing part of the Hmga2 gene is cut short and replaced with DNA from another chromosome. Biologists have mostly focused on the shortened protein as the possible reason that the cells with this DNA swap became tumors. But this DNA swap removes not only the gene's protein-producing regions but also those areas that do not code for protein. Furthermore, these non-protein-producing regions contain the elements that microRNAs recognize.

According to the researchers, in the non-protein-producing region, Hmga2 has seven sites that are complementary to the let-7 microRNA, a microRNA expressed in the later stages of animal development. Dr. Mayr wondered whether loss of these let-7-binding sites, and therefore loss of regulation by let-7 of Hmga2, might cause overexpression of Hmga2, which in turn would result in tumor formation.

To find out if this was the case, Dr. Mayr created a series of Hmga2 in which various numbers of let-7 sites were destroyed. She discovered distinct evidence that when exposed to let-7, the fewer sites that were intact, the more protein was generated. Next, she evaluated whether disrupting let-7's ability to suppress Hmga2 would lead toward tumor creation. In a standard in vitro test of cancer-causing genes, colonies of mouse cells that expressed normal or shortened Hmga2 did not grow significantly, while cells in which Hmga2 contained disrupted let-7 sites did. In fact, the more that let-7 sites were damaged the greater the number of colonies.

Dr. Mayr also worked with MIT assistant professor Dr. Michael Hemann to inject these cells in mice with a compromised immune system. The scientists found that the mice with cells that expressed the version of Hmga2 with the disrupted let-7 sites developed tumors.

Overall, the results highlight a new mechanism for cancer formation. Hmga2, and possibly certain other genes that are normally regulated by microRNAs, can help give rise to tumors if a mutation in the gene disrupts the microRNA's ability to regulate it. Moreover, the findings demonstrate that the interaction of one microRNA with one of its target genes can produce a certain trait in mammals. This is important because scientists are only beginning to learn the functions of microRNAs in animals.

"Because hundreds of human genes appear to be regulated by the let-7 microRNA, we were afraid we wouldn't see any difference when we changed only one of these target genes,” said Dr. Bartel, who is also an MIT biology professor. "Seeing the difference encourages us to explore the biological importance of other examples of microRNA regulation.”


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