By Kevin Davies
July 20, 2005 | A trio of studies published in the June 9, 2005, issue of Nature demonstrates that tiny fragments of RNA — so-called microRNAs — can cause cancer. The results, from groups at Cold Spring Harbor Laboratory in New York, MIT, Harvard Medical School, and the Johns Hopkins University School of Medicine, mark the opening of an exciting new chapter in cancer research. NIH researcher Paul Meltzer says that these “change the landscape of cancer genetics.”
For decades, cancer research has focused on oncogenes that encode cancer-causing proteins that wreak havoc with normal cell growth and division by various mechanisms. “Now,” says University of North Carolina’s Scott Hammond, a study co-author, “we have to at the very least also consider noncoding genes for miRNAs, when we think about the kinds of genetic alterations that can contribute to tumors.”
MicroRNAs (miRNAs) are tiny RNA molecules of about two-dozen nucleotides in length. More than 200 such entities have been catalogued in recent years, attracting intense interest in the fields of gene regulation and RNA interference. But while there have been hints that miRNAs might be associated with certain cancers, the new studies unequivocally show that to be the case.
In one study , Howard Hughes Medical Institute (HHMI) investigators Todd Golub (Broad Institute) and Bob Horvitz (MIT) developed a new bead-based detection platform to show that miRNA expression profiles can be used to classify cancers.
The researchers ruled out conventional microarray methods because the short miRNA fragments lack the specificity to produce a clean signal due to nonspecific hybridization. So Golub’s group improvised, attaching DNA probes corresponding to various miRNAs to color-coded plastic beads, provided by Luminex Corp. The beads are tagged with variable mixtures of fluorescent dyes, enabling the identification of different miRNAs. The amplified miRNAs are passed over the beads and stained, and a flow cytometer measures miRNA identity and abundance.
Surprisingly, the miRNA expression patterns proved a highly reliable and specific predictor of cancer types, including cancers that are difficult to distinguish under the microscope. Golub’s team also found that the technique could distinguish tumors from normal cells — most miRNAs are suppressed in tumors. Additional studies in mouse cancer models showed that the technique could distinguish cancerous and normal cells from the same organism.
Horvitz, who shared the Nobel Prize for Physiology or Medicine in 2004, has speculated about the possible role for miRNAs in cancer since they were implicated in the control of cell division in the nematode Caenorhabditis elegans. “Our collaborative study establishes a striking correlation between patterns of microRNA expression and cancer,” Horvitz says, “and offers the prospect of using microRNA expression patterns to help in the diagnosis and treatment of cancer.”
“A modest number of miRNAs (about 200 in total) might be sufficient to classify human cancer,” conclude Golub and colleagues. “Moreover, the bead-based miRNA detection method has the attractive property of being not only accurate and specific but also easy to implement in a routine clinical setting.”
In a second paper , Cold Spring Harbor/HHMI researchers Gregory Hannon and Scott Lowe, together with Hammond, demonstrate that a group of microRNAs causes B-cell lymphomas in mice. The researchers compared the activity of genes for seven linked mi-RNAs called mir-17-92 in healthy mice and animals with B-cell lymphoma. (The genes for these miRNAs are located within a gene segment on chromosome 13 that is commonly amplified in lymphoma cells.)
Hammond’s team found a significant increase in expression in the lymphoma mice, as well as in human lymphoma samples. It also found that overexpressing the mir-17-92 genes in a mouse cancer model accelerated tumor development and death in those animals. “This is by no means a final answer about the role of miRNAs in cancer,” Hannon says. “But it’s the first really definitive link where we can show with biological experiments that microRNAs can act as an oncogene.”
Hammond and co-authors support the proposal that cancer-causing mi-RNAs be dubbed “oncogenic micro-RNAs,” or “oncomiRs.”
In a third paper , Joshua Mendell and colleagues at The Johns Hopkins University School of Medicine reported that some microRNAs cooperate with a gene already known to cause human cancers.