MicroRNAs show promise for detecting, treating cancer
(4 July 2009: VIDYYA MEDICAL NEWS SERVICE) -- Since James Watson and Francis Crick discovered the structure of DNA over 50 years ago, successive experiments by thousands of researchers worldwide have led to the central dogma of molecular biology: genes (DNA) encode RNA, which in turn directs the assembly of proteins. The hundreds of thousands of unique proteins produced by our genetic code in turn drive the workings of the body, including the regulation of which genes are expressed, when, and in what tissues.
The relatively recent discovery of small functional RNAs, including a class of tiny RNAs barely more than 20 nucleotides in length called microRNAs, has upended the long-held belief that nucleotides are only passive carriers of genetic information. MicroRNAs, it turns out, are non-coding RNAs. They do not pass on the instructions for assembling proteins but, instead, act like proteins, serving as potent regulators of gene expression. MicroRNAs bind to messenger RNAs (mRNA), either blocking the translation of the mRNAs or targeting them for destruction by the cellular machinery.
MicroRNAs are now thought to regulate the expression of more than half of all mammalian genes, including those responsible for cellular processes such as cell growth (proliferation) and cell death (apoptosis). When these processes spiral out of control due to faulty regulation, the result can be cancer.
An Exploding Field in Cancer Research
“I think microRNAs are probably the most significant discovery in the last 10 years in molecular biology, in terms of understanding how the gene expression process and the cellular machinery are regulated,” said Dr. Daniel Gallahan, deputy director of NCI’s Division of Cancer Biology (DCB). “You’re now constantly seeing the discovery of new microRNAs associated with the cancer process.”
These discoveries began in 2002, when the laboratory of Dr. Carlo Croce, director of the Human Cancer Genetics Program at the Ohio State University, showed that two microRNAs are deleted or downregulated (their expression is decreased) in the majority of cases of chronic lymphocytic leukemia. This was the first discovery of aberrant microRNA expression in a human cancer, and it opened a floodgate of research in the field. To date, aberrant microRNA expression has been found in every tumor type tested and has also been implicated in cancer progression and metastasis.
Researchers are now studying how this knowledge can be applied in the cancer clinic. Because microRNAs are very specific for different types of tissues—the brain contains different microRNAs than the liver or the bladder—and even for types of cells within those tissues, researchers have been looking for diagnostic applications for the molecules. “I think there is no doubt that microRNAs will be exploited for diagnostic and prognostic purposes,” said Dr. Croce.
For example, in a recent study, microRNA signatures were able to distinguish the correct tissue for cancers of unknown primary origin with more than 90 percent accuracy. “This effort compares favorably with the best result so far using mRNA-expression levels and will probably continue to improve as larger sample sets are collected and profiled for expression of microRNAs,” concluded the authors, led by Drs. Nitzan Rosenfeld and Ranit Aharonov from Rosetta Genomics in Israel.
The role of microRNAs in carcinogenesis also makes them a promising target for treatment. Especially attractive is the fact that one microRNA can regulate many, even hundreds, of gene targets. Scientists have estimated that more than 1,000 individual microRNAs exist in humans, but very few of their targets have been identified to date.
“The field is grappling to understand whether these very potent phenotypes controlled by microRNAs are related to a few targets that are regulated very robustly, versus many targets that are regulated only subtly. There’s also a spectrum between those possibilities,” explained microRNA researcher Dr. Joshua Mendell, associate professor of Pediatrics and Molecular Biology and Genetics at Johns Hopkins University.
But if the microRNAs driving carcinogenesis can be identified, finding their targets may not be essential for exploring them therapeutically. In a proof-of-concept study in mice, Dr. Mendell and his colleagues recently showed that restoring the normal expression of a single microRNA in liver cancer cells was enough to induce tumor regression, even though the microRNA did not target the cancer gene that initiated the tumors. The technique used was completely nontoxic to normal liver cells, which already expressed the microRNA.
This concept holds promise for treating tumors driven by cancer genes that have proven extremely difficult to target, so called “undruggable targets” such as the gene KRAS. “In cancers in which we cannot target a specific gene, we might be able to take a shortcut and target the downstream microRNAs that are disregulated—basically target the consequence of that genetic mutation,” explained Dr. Croce.
In response to the exponential growth of research and interest in microRNAs, DCB recently held a 2-day MicroRNA in Cancer Biology think tank, bringing together scientists engaged in leading-edge research in the field of microRNA biology.
“We wanted to identify where the field was going and figure out if there was anything we can do to facilitate that work,” said Dr. Gallahan.
The participants identified many areas that could help rapidly advance microRNA research, including “better algorithms for predicting microRNA targets, systematic sequencing of known microRNAs, and transgenic mouse models, which could be used to understand the roles individual microRNAs play in cancer. And of course ways to fund and share these resources,” explained Dr. Chamelli Jhappan, program director in DCB’s Tumor Biology and Metastasis Branch, who organized the think tank.
The full report from the think tank will be available on the DCB Web site by the end of the year. Those who would like to be on a distribution list for the report may contact Dr. Jhappan at firstname.lastname@example.org.
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