Silencing Small but Mighty Cancer Inhibitors
December 10, 2007
Researchers from Johns Hopkins and the University of Pennsylvania
have uncovered another reason why one of the most commonly activated
proteins in cancer is in fact so dangerous. As reported in Nature
Genetics this week, the Myc protein can stop the production of at
least 13 microRNAs, small pieces of nucleic acid that help control
which genes are turned on and off.
What's more, in several instances, re-introducing repressed miRNAs
into Myc-containing cancer cells suppressed tumor growth in mice,
raising the possibility that a sort-of gene therapy approach could be
effective therapy for treating certain cancers.
A research team led by Joshua Mendell, M.D., Ph.D., assistant
professor at the McKusick-Nathans Institute of Genetic Medicine at
Johns Hopkins, previously found that Myc could turn on one particular
group of growth-promoting miRNAs called the miR-17-92 cluster in
lymphoma cells. His team, along with Andrei Thomas-Tikhonenko's lab
at the University of Pennsylvania, now took a broader approach and
analyzed more than 300 miRNAs in both human and mouse lymphoma cells.
In those cells that had high amounts of Myc protein, the researchers
found significant changes in the quantities of at least 13 miRNAs.
"The surprising aspect, considering our miR-17-92 results," says
Tsung-Cheng Chang, lead author on the study, "is that lots of Myc
turns everything off, not on."
When they looked closer at the DNA of the lymphoma cells, the team
also found that Myc was directly attaching to the DNA at the miRNA genes.
"This was further evidence that the decrease in miRNA levels was
directly due to the action of Myc," says Chang.
"This study expands our understanding of how Myc acts as such a
potent cancer-promoting protein," says Mendell. "We already knew that
it can directly regulate thousands of genes. Through its repertoire
of miRNAs, Myc likely influences the expression of thousands of
additional genes. Activation of Myc therefore profoundly changes the
program of genes that are expressed in cancer cells."
"Still, we needed to determine whether any of these Myc-regulated
microRNAs played a direct role in cancer," adds Thomas-Tikhonenko.
His team then individually reintroduced several of the repressed
miRNAs into mouse lymphomas that also had high levels of Myc and
measured the effect on lymphoma progression in animals. They found
that more than five of the miRNAs could stop cancer growth.
"While this result was not entirely surprising, we had no idea that
cancer suppression by
microRNAs could be so powerful," admits Thomas-Tikhonenko. Mendell
also notes that RNA-based therapies have had some success in animal
models, and researchers might potentially find a wide range of miRNAs
that can stop cancers in their tracks.
The research was funded by the National Institutes of Health.
Authors on the paper are Duonan Yu and Andrei Thomas-Tikhonenko of
the University of Pennsylvania and Tsung-Cheng Chang, Yun-Sil Lee,
Erik Wentzel, Dan Arking, Kristin West, Chi Dang and Joshua Mendell
of Johns Hopkins.
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