It’s been almost two years since groundbreaking research published in Nature confirmed the definitive link between microRNAs and cancer. Today, the field is still expanding as more and more research aims to locate specific miRNA targets and their mechanisms of action. At the annual American Association for Cancer Research conference in April, a full auditorium listened to several miRNA experts talk about current research implicating miRNAs as both potential oncogenes and tumor suppressors.
Scott Hammond, who heads up research on miRNAs at the University of North Carolina School of Medicine, led the symposium, speaking about his current research on the relationship between miRNA expression and the propagation of tumor stem cells. About 450 miRNAs have been identified in the human genome, he says, and since each miRNA targets as many as 100 mRNA transcripts, more than 45,000 mRNAs are targeted.
The RNAi pathway is one way that a cell reacts to invasive viruses, by targeting dsRNA for degradation and then using these degraded RNA molecules to silence complementary mRNAs that are circulating in the cytoplasm. MicroRNAs act as endogenous silencers, quashing expression by targeting complementary endogenous mRNAs, binding to them and repressing their translation into proteins, or destroying them.
Christine Mayr, a postdoc in David Bartel’s lab at the Whitehead Institute at MIT who also spoke at the AACR session, recently published a paper on the oncogenic effect of a specific miRNA, let-7. Bartel’s group found that turning off let-7’s usual repression of the High Mobility Group A2 (Hmga2) protein promotes oncogenic transformation and subsequent tumor growth.
Most genes targeted for study are known oncogenes that are overexpressed in cancer, Mayr says. However, “it has its limitations,” she adds. “You limit yourself to oncogenes which have already been shown to play a role.”
Another limitation so far has been the tendency of research to focus on conserved targets, or mRNAs or mRNA sites that are known to be phylogenetically conserved. Looking at nonconserved sites could open doors to discovering many more such regulatory non-coding genes. “If you take, for example, nonconserved miRNA binding sites,” Mayr says, “nearly every gene could be regulated theoretically by miRNAs. We are really at the beginning in the whole field.”
Not only will locating specific mRNA binding sites be helpful in predicting novel drug targets, tumor miRNA expression profiles can be useful for identifying poorly differentiated tumors. Determining whether miRNAs act mainly to “fine-tune” gene expression or more often as on/off switches is a question that looms large, especially when it comes to the potential therapeutic application of miRNAs.