MIT Researchers Demonstrate Protective Role Of MicroRNA - Genetic Snippets Linked To Cancer Also Key To Embryonic Cell Development

Main Category: Biology / Biochemistry
Also Included In: Cancer / Oncology
Article Date: 07 Mar 2008 - 12:00 PDT

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Snippets of genetic material that have been linked  to cancer also play a critical role in normal embryonic development  in mice, according to a new paper from MIT cancer biologists.

The work, to be reported in the March 7 issue of Cell, shows that a  family of microRNAs-short strands of genetic material-protect mouse  cells during development and allow them to grow normally. But that  protective role could backfire: the researchers theorize that when  these microRNAs become overactive, they can help keep alive cancer  cells that should otherwise die - providing another reason to target  microRNAs as a treatment for cancer.

Discovered only a decade ago, microRNAs bind to messenger RNAs  (mRNAs), preventing them from delivering protein assembly  instructions, thereby inhibiting gene expression. The details of how  microRNAs act are not yet fully understood.

"The scientific community is busy trying to understand what specific  biological functions these microRNAs affect," said Andrea Ventura,  lead author of the paper and postdoctoral associate in the Koch  Institute for Integrative Cancer Research at MIT (formerly known as  the Center for Cancer Research).

Ventura, who works in the laboratory of Tyler Jacks, director of the  Koch Institute, and colleagues studied the function of a family of  microRNAs known as the miR-17~92 cluster.

Previous research has shown that the miR-17~92 cluster is overactive  in some cancers, especially those of the lungs and B cells.

To better understand these microRNAs' role in cancer, the researchers  decided to study their normal function. Knocking out microRNA genes  and observing the effects can offer clues into how microRNA helps  promote cancer when overexpressed.

They found that when miR-17~92 was knocked out in mice, the animals  died soon after birth, apparently because their lungs were too small.  Also, their B cells, a type of immune cell, died in an early stage of  cell development.

This suggests that miR-17~92 is critical to the normal development of  lung cells and B cells. In B cells these microRNAs are likely acting  to promote cell survival by suppressing a gene that induces cell  death, said Ventura.

"Understanding why these things are happening provides important  insight into how microRNAs affect tumorigenesis," he said.

The researchers theorize that when miR-17~92 becomes overactive in  cancer cells, it allows cells that should undergo programmed cell  death to survive.

Blocking microRNAs that have become overactive holds promise as a  potential cancer treatment. Research is now being done on molecules  that prevent microRNAs from binding to their target mRNA.

More work needs to be done to make these inhibitors into stable and  deliverable drugs, but Ventura said it's possible it could be done in  the near future.

The exact genes targeted by miR-17~92 are not known, but one strong  suspect is a gene called Bim, which promotes cell death. However, a  single microRNA can have many targets, so it's likely there are other  genes involved.

The researchers also studied the effects of knocking out two other  microRNA clusters that are closely related to miR-17~92 but located  elsewhere in the genome.

They found that if the other two microRNA clusters are knocked out  but miR-17~92 remains intact, the mice develop normally. However, if  miR-17~92 and one of these similar clusters are removed, the mice die  before birth, suggesting there is some kind of synergistic effect  between these microRNA families.

Other MIT authors of the paper are Amanda Young, graduate student in  biology; Monte Winslow, postdoctoral fellow in the Center for Cancer  Research (CCR); Laura Lintault, staff affiliate in the CCR; Alex  Meissner, faculty member at the Broad Institute of MIT and Harvard;  Jamie Newman, graduate student in biology; Denise Crowley, staff  affiliate at the CCR; Rudolf Jaenisch, professor of biology and  member of the Whitehead Institute for Biomedical Research; Phillip  Sharp, MIT Institute Professor; and Jacks, who is also a professor of  biology.

The research was funded by the National Institutes of Health and the  National Cancer Institute.

 http://www.mit.edu