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One Man's Junk DNA Is Another Man's Treasure: MicroRNAs and the Next Big Thing in Cancer Prognosis

Until very recently, scientists thought they had a pretty good basic model for how cells work. DNA was the storehouse of all information, the blueprint for life. Proteins were the building blocks: the bricks, mortar, and switches that actually made a living thing and also made it work. According to the model, while RNA did a good job shuttling the DNA’s instructions from the nucleus to the cytoplasm, it did not serve any larger purpose. And the long stretches of DNA that did not contain information for building proteins were unimportant.

In 1993, scientists started to find the first hints that this long-standing model of how life works might not explain everything. Researchers studying Caenorhabditis elegans worms started finding evidence that short 18–25 nucleotide-long snippets of RNA produced from genes that did not encode protein might be bigger players in the workings of cells than had been realized. These snippets started turning up in a number of different species, showing remarkable conservation and suggesting that some fundamental piece of the cell was starting to make itself known (Figure 1).

Fast forward to the present day. The importance of these short RNA pieces—now dubbed microRNAs—as epigenetic regulators of cell development, survival, and disease is becoming ever clearer. And their popularity as a research topic has exploded. “The basic science of microRNAs is just fascinating,” said Curtis Harris, M.D., Chief of CCR’s Laboratory of Human Carcinogenesis, who studies microRNAs as prognostic tools in cancer. “How the microRNA is processed from its gene, its function in normal cell biology, in development, and in disease— since microRNAs are relatively newly discovered, all of these features are still being worked out.” A search of the PubMed database turned up 2,611 papers published on microRNAs since 2001, with 1,027 published in 2007 alone.

The links between microRNAs and cancer are also now well appreciated. “The cancer field has now become very excited by microRNAs, in part because they are so new,” noted Harris. Cancer researchers also have a clearer view of microRNAs as actors in carcinogenesis. Based on this knowledge, researchers like Harris are investigating how to turn our growing knowledge of microRNAs into clinical tools for cancer prognosis and therapy.

Shooting the Messenger

MicroRNAs are like transcription factors for RNA. Just as transcription factors control a gene’s transcription into messenger RNA, microRNAs control a messenger RNA’s translation into protein. But instead of promoting gene expression, as transcription factors do, microRNAs impede it: MicroRNA-bound messenger RNAs do not get translated, effectively silencing the gene from which they were transcribed. “MicroRNAs bind to the messages of protein-coding genes, either changing the stability of that message or the translation of that message into protein,” explained Harris.

The number of microRNA genes tucked away in the genome is unclear, but by some estimates there may be as many as a thousand. Researchers estimate conservatively that about one-third of all protein-coding genes may be controlled to some extent by microRNAs. They can have such widespread effects because they tend to act globally. “Because they are short and their ‘seed’ sequences [the first six nucleotides in a microRNA, which act as binding sites] are somewhat degenerate, they physically interact with messages that they don’t exactly match,” Harris noted. “So a single microRNA may target 10, 50, maybe even a 100 messages in different genes or pathways.”

A search of the PubMed database turned up 2,611 papers on microRNAs since 2001, with 1,027 published in 2007 alone.

Drawing the Lines

The first paper suggesting a link between microRNAs and cancer, published in 2002 by a colleague of Harris, The Ohio State University’s Carlo Croce, M.D., reported that a genomic region deleted in about half of all cases of B-cell chronic lymphocytic leukemia (B-CLL) housed genes for two microRNAs. The development of techniques for microarray and bead-based flow cytometry analyses of microRNA expression soon led to the discoveries of microRNA signatures unique to specific tumors and their cellular origins.

Figure 1. The roles of microRNAs—simple short pieces of RNA that do not encode protein—in the control of nearly all critical cellular processes have gained widespread and rapid appreciation.

As the research on microRNAs and cancer has gone deeper, particular microRNAs have begun to stand out as potentially causative agents. For instance, microRNAs called miR-155 and the miR-17-92 cluster act like oncogenes, while miR-15a and miR-16-1 appear to function as tumor suppressors. The genetic lesion Croce identified in B-CLL included the genes encoding miR-15a and miR-16-1.

“We are finding that microRNAs can serve a range of purposes in the context of cancer and cancer treatment,” said Harris. “They can tell us a lot about the basic biology of cancer and about what pathways are involved and what might be good targets for therapeutic development. One can, at least in preclinical studies, knock down the expression of a specific microRNA with an antisense strategy and see an anti-tumor effect. They can also be good clinical biomarkers, useful tools for diagnosis and, maybe, for predicting therapeutic outcome.”

Translating Science Together

It was the role of microRNAs as developmental players in cancer, combined with Croce’s B-CLL paper, that gave Harris his entrée into the world of microRNAs. “When Carlo made what I think was a seminal observation that microRNAs were associated with cancer, that seemed to be a very exciting finding and one that I thought might have relevance to solid tumors.”