RNA interference (RNAi) is a natural process that uses small double-stranded RNA molecules to control, and turn off, gene expression. In RNAi, double-stranded RNA that matches the messenger RNA produced by a given gene degrades that messenger RNA, in effect wiping out the function of that gene in a cell.
The first research on RNAi was published in 1998 when Andrew Fire, Ph.D., professor of pathology and genetics at Stanford University, demonstrated that double-stranded RNA injected into worms could turn off genes. He would win a Nobel Prize in 2006 for his work.
Just three years later, in 2001, a group led by Tom Tuschl, Ph.D., head of the laboratory for RNA Molecular Biology at Rockefeller University, proved small interfering RNA (siRNA) could silence genes containing complementary sequences in human cells. This study raised the possibility for the first time that RNAi could be used as a drug.
The use of siRNA in therapy came closer to a reality in a paper published in Nature in 2004, when researchers at Anylam, a company originally founded by Nobel Laureate Philip Sharp of the Massachusetts Institute of Technology and others, injected RNAi compounds attached to cholesterol in mice, silencing genes that helped lower cholesterol. This was the first time gene silencing was done in live animals by a systemic route.
RNAi in Cancer
In cancer research, it is becoming routine to use RNAi as a tool to study-and manipulate-a particular gene and its function. The technology can be applied to cancer cells or primary tumor cells and to a broad range of model systems, including animals. RNAi is particularly useful for characterizing molecular targets, screening genes and looking at gene interactions with specific drugs, making it indispensible to the field of pharmacogenomics.
In 2007, scientists at Abbot Labs used RNAi as a tool to functionally evaluate genes that play a role in maintaining human tumor cell survival. They determined that Ran and TPX2 preferentially reduced the survival of cells that had been transformed by K-Ras, a known oncogene, and therefore these two genes may be a potential therapeutic target.
Scientists in the field are also studying the link between RNAi and alterations at the DNA level in regulating gene expression in a number of organisms, such as yeast, fruit flies and plants. Some scientists believe that RNAi plays a role in triggering potentially long-term changes in gene expression by modifying chromatin, the stuff of chromosomes.
MiRNA in Cancer
MicroRNA (miRNA), discovered some 15 years ago in studies of roundworms, are small non-coding, regulatory RNAs encoded in the genome that seem to play a role in embryonic development, and together may comprise a network that controls genes and protein production throughout the body. With more than 250 in the human genome, they are transcribed into short hairpin RNA that is processed to produce a 21- or 22-nucleotide RNA that pairs with target messenger RNA, silencing it at the level of translation. Specifically, miRNA does not code for a protein, but, instead, causes the destruction of coding RNA, disrupting its activity to prevent protein production.
Scientists believe miRNA may play a major role in controlling overall gene expression and the cancerous process. A pair of studies in 2004 and 2005 reported that as much as 20 percent of cellular RNAs are likely to be regulated by miRNAs, providing further evidence of a new, important gene expression regulatory system.
Researchers at the University of North Carolina in Chapel Hill compared mice genetically engineered to overproduce the oncogene protein c-myc, which has been implicated in lymphoma, with similar mice altered to produce extra miRNA found in lymphoma cells. Most of the mice with extra c-myc but not miRNA lived for more than 100 days; mice with too much c-myc and miRNA developed lymphoma within 50 days and died shortly afterward.
In 2008, scientists from Ohio State University showed that a global increase in the transcription of miRNA genes occurred in cirrhotic and hepatitis-positive livers and that miRNA expression may be a useful tool for determining outcomes in hepatocellular carcinomas.
Another 2008 study showed that the presence of certain miRNA associated genes were associated with increased risk for bladder cancer. Specifically, GEMIN4 was linked with a 25 percent increased risk of bladder cancer.