National Cancer Institute
Our understanding of the role that RNA plays in cellular processes and in cancer has evolved rapidly this century. Messenger, transfer, and ribosomal RNA are still vitally important to the cell as a translation mechanism, but regulatory RNAs are now known to play a very important role as well. MicroRNA can block translation or accelerate cellular degradation and small interfering RNAs (siRNA) can act in a similar manner. And there are a number of other types of RNA that can play an important role in activating or blocking important cancer pathways.
The regulation of gene expression by microRNAs and siRNAs is called RNA interference, or RNAi, for short. This phenomenon has recently been exploited to develop molecular tools for cancer research. By injecting short strands of RNA molecules into cells, scientists are now able to silence, or turn off, certain genes. This technique allows experiments, which used to take months or years, to be completed in weeks or even days.
Use of RNAi has also been enabled by new generations of highly-efficient, cost-effective, high-throughput genetic screening techniques that make it possible to identify genes associated with cancer. Isolating genes that control disease progression will lead to identification of potential targets and, in turn, to new targeted cancer therapeutics.
“High-throughput sequencing will change everything. It will tell us about the cell state in the tissue, and not in just cell lines,” said Nobel Laureate Phillip A. Sharp, Ph.D., of the David A. Koch Institute for Integrative Cancer Research at MIT. “We are going to accelerate the rate at which we’re going to be able to effectively treat cancers, and I think we will find ourselves in a 10 to 15 year window where we will see that many of the cancers that develop in mid-aged and young people will be treatable for very long periods of time.”
RNAi can also be used to investigate the mechanism of action of drugs that are, for reasons unknown, effective against cancer. In addition, RNAi screening can be used to identify genes that enhance the ability of chemotherapy to fight cancer.
“We need to look, at a basic level, at particular cells and particular states, as that’s the only way to design drugs and interventions,” continued Dr. Sharp. “This wasn’t possible in the pre-genome era — we didn’t have enough granularity and now we do, so we’ve got a specific way of intervening.”
One particular area of study, the regulation of gene activity by methylation, could benefit from advances in RNAi techniques. Methylation involves the addition of methyl groups (molecules made up of one carbon atom with three hydrogen atoms attached) to DNA or proteins. Stephen Baylin, M.D., and his team at Johns Hopkins University are very involved in the field of epigenetics, which centers around methylation, and they are looking at how gene expression may be caused by mechanisms other than changes in the underlying DNA sequence. The researchers used high-throughput screening techniques to study a large pool of genes thought to be involved in cancer. Their aim was to identify genes with potential prognostic value. They found that 36 of 189 genes they had previously identified as being associated with breast or colon tumor development were often hypermethylated. RNAi techniques may allow them to confirm or refine their findings.
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