Dr. Gregory Hannon, CSHL
Over the past few years, scientists have discovered that a new class of genetic regulators called "microRNAs" influences normal human growth and development. Now, researchers at Cold Spring Harbor Laboratory (CSHL) and their colleagues have found that microRNAs also play an important role in human cancer. The findings are published in today's issue of the journal Nature.
" These studies change the landscape of cancer genetics," says cancer expert Dr. Paul Meltzer, who did not participate in the studies.
In one of the new studies, researchers at Cold Spring Harbor Laboratory, led by Howard Hughes Medical Institute investigator Dr. Gregory Hannon, and at the University of North Carolina, Chapel Hill, led by Dr. Scott Hammond, focused on a segment of human chromosome 13 that was known to be amplified (i.e. present in excess) in several tumor types including B-cell lymphoma. The researchers observed that this DNA segment, referred to as the mir-17-92 cluster, has the potential to encode seven microRNAs.
To determine whether excess expression of microRNAs encoded by the mir-17-92 cluster might be involved in cancer, the scientists first examined whether one or more of the microRNAs was expressed at abnormally high levels in four B-cell lymphoma cell lines in which the mir-17-92 cluster was amplified, compared to normal B-cells and to five leukemia and lymphoma cell lines in which the mir-17-92 cluster was not amplified.
The researchers found that indeed, five microRNAs encoded by the mir-17-92 cluster were overexpressed specifically in the B-cell lymphoma cell lines bearing an amplified mir-17-92 cluster.
Next, the scientists examined the expression levels of the mir-17-92 microRNAs in human tumor biopsies including 46 lymphomas and 47 colorectal carcinomas. They observed significant (greater than fivefold) overexpression of the mir-17-92 microRNAs in 65% of the lymphomas, with an average mir-17-92 microRNA overexpression of 10-fold in those lymphomas (and a high of 82-fold microRNA overexpression). In contrast, 15% of the colorectal carcinomas displayed greater than fivefold mir-17-92 microRNA overexpression.
" These findings suggested that mir-17-92 microRNA overexpression might contribute to human cancer, particularly to B-cell lymphoma but also to other forms of the disease," says Hannon. "And they gave us confidence that we might be looking at something that would be clinically relevant."
To test that idea directly, the researchers examined whether elevated expression of mir-17-92 or other microRNAs could accelerate the onset of cancer and/or decrease survival in a mouse model of B-cell lymphoma.
As expected, control animals developed B-cell lymphoma after about 2 months, and the overall survival of this group (n = 12) after 3 months was 75%.
In stark contrast, animals in which the mir-17-92 microRNAs were overexpressed experienced accelerated development of B-cell lymphoma (40 days compared to 2 months), and--significantly--none of the animals in this group (n = 14) survived after 3 months, compared to the 75% survival rate of the control animals in which the mir-17-92 microRNAs were not overexpressed.
Moreover, tumors induced in mir-17-92 microRNA-overexpressing animals consistently invaded organs outside the lymphoid compartment (including liver, lung, and kidney), and lacked the extensive "programmed cell death" or apoptosis observed in the control tumors and which helps keeps tumors in check. These findings indicate that overexpression of the mir-17-92 microRNAs can contribute to highly malignant tumors.
Collectively, the results of the study establish that microRNAs can function as bona fide oncogenes, leading the researchers to propose that such oncogenic microRNAs be designated "oncomiRs," with mir-17-92 being oncomiR-1.
“ This is by no means a final answer about the role of microRNAs in cancer,” says Hannon. “But it's the first definitive demonstration that microRNAs can act as oncogenes.”
For more information, visit www.cshl.edu.