According to Golub, a key biological question is whether the distinctive miRNA profiles they have found in cancers represent causation of cancer by miRNAs, or merely an association.
However, in their Nature paper, Hannon, Lowe, Hammond and their colleagues, established a clear causative role for a specific cluster of miRNAs in the blood cancer B-cell lymphoma. In their study, they compared normal human cells and tissues to those with B-cell lymphomas in their expression of the genes for a cluster of miRNAs called mir-17-92. Studies by other researchers had shown that the gene region, or locus, containing this cluster is amplified in several types of lymphoma.
Using a custom microarray technique developed recently by Hammond, the researchers found that the tumors showed substantial increase in activity of the cluster of miRNA genes.
Next, working with co-author Scott Powers of Cold Spring Harbor, Hannon and his colleagues tested the mir-17-92 miRNA gene activity in human tumor samples of lymphoma and colorectal cancers. They found overexpression of the miRNA genes in the former but not the latter. "That finding gave us confidence that we might be looking at something that would be clinically relevant," said Hannon
Finally, the researchers tested the effects of overexpression of the miRNA cluster in mice carrying the oncogene c-myc -- employing a mouse model often used by Lowe and his colleagues.
"Although the c-myc mice develop tumors, we found that overexpressing the mir-17-92 locus in those mice caused the tumors to arise much more quickly, be much more aggressive and kill the animals faster," said Hannon. Specifically, he said, the addition of the miRNA genes appeared to reduce the natural
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Contact: Jim Keeley
keeleyj@hhmi.org
301-215-8858
Howard Hughes Medical Institute
8-Jun-2005