Studying these cells could lead to new treatments for diseases ranging from gastrointestinal disease to diabetes.
A microRNA directly regulates a gene implicated in human cancers, researchers from the Whitehead Institute and MIT reported in the Feb. 22 online issue of Science.
MicroRNAs are tiny snippets of RNA that can repress activity of a gene by targeting the gene's messenger RNA (which copies DNA information and starts the process of protein production).
The first microRNA was discovered in 1993, in worms. It took seven years for the second one to be found, also in worms. But then the floodgates burst. Many microRNAs now have been found in diverse plants and animals, including hundreds in humans. Moreover, microRNAs found in mammals regulate more than a third of the human genome, as shown in a 2005 study by MIT Professor of Biology David Bartel and colleagues. Bartel is also a Whitehead member and Howard Hughes Medical Institute investigator.
But given the wealth of microRNAs and the ability of individual microRNAs to target hundreds of genes, researchers have struggled to show the biological impact of a particular microRNA on a particular target in mammals (although such connections have been shown in plants, worms and flies). Several groups have demonstrated that over-expression or under-expression of a microRNA can play a role in certain cancers, but have not clarified the genes responsible.
Looking to find a promising target for an individual microRNA, Christine Mayr, a postdoctoral researcher in the Bartel lab, picked 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 don't code for protein. And these non-protein-producing regions contain the elements that microRNAs recognize.
It turns out that 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. Mayr wondered whether loss of these let-7 binding sites, and therefore loss of regulation by let-7 of Hmga2, might cause over-expression of Hmga2 that in turn would result in tumor formation.
To find out, Mayr created a series of Hmga2 genes in which various numbers of let-7 sites were destroyed. She found clear evidence that when exposed to let-7, the fewer sites that were intact, the more protein was produced.
Next, she tested whether disrupting let-7's ability to repress Hmga2 would lead to 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.
Mayr also worked with MIT Assistant Professor Michael Hemann of the Department of Biology 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 perhaps 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. In addition, the results show 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," says Bartel. "Seeing the difference encourages us to explore the biological importance of other examples of microRNA regulation."
This research was funded by the National Institutes of Health.