miRNA emerge as a class of gene regulators

Feb 7 2006

Scientists have discovered that a wide variety of different cancers actually share something in common - a molecular "signature" made up of tiny bits of genetic material called microRNA (miRNA) that target key cancer genes and promote malignant growth.

The finding provides more insight into miRNA as an emerging class of gene regulators and may also pave the way for new approaches in diagnosis and treatment.

The study appears online in the Proceedings of the National Academy of Sciences.

Scientists have only recently begun to understand how important microRNA may be in regulating gene expression. For years, these tiny bits of genetic material went unnoticed - nestled within vast stretches of the genome that appeared to be non-functional. They may have been easy to overlook: miRNAs are usually only 22 or so nucleotides in length - miniscule in size when compared to their cousins, messenger RNA, which can be several hundred to a thousand times that long.

But several years ago, researchers studying roundworms noted that properly functioning miRNA was necessary for normal development. Since then, scientists in laboratories around the world have identified hundreds of miRNAs and found that they are highly conserved over time - meaning that they show up in generation after generation in everything from plants to mice to humans - confirming their important roles in growth and survival.

Carlo Croce, professor and chair of molecular virology, immunology and medical genetics at The Ohio State University and the first researcher to discover miRNA involvement in human cancer, had a hunch that there might be shared patterns of miRNA among certain cancers. Under his direction, researchers looked for miRNA activity, or expression, in 540 samples of lung, breast, stomach, prostate, colon and pancreatic tumors and in the normal tissue surrounding them.

Using microarray technology developed at Ohio State , lead investigators Stefano Volinia and George Calin found 137 different miRNAs expressed in at least half of the cancers, with 43 miRNAs allowing scientists to distinguish the difference between normal and malignant tissue.

Further tests showed that 21 of the distinguishing miRNAs were deregulated in at least three of the cancers - and in some cases, as many as five or all six. The researchers defined this limited set as the "miRNA signature" in solid tumors.

Croce says finding such a signature is important because it shows that many forms of cancer share common genetic pathways that become scrambled as cancer takes hold and spreads. He says narrowing the list of the most active ones provides a guide to directing future research.

"We know that there are hundreds of miRNAs, and some of them may have multiple gene targets. Finding the ones that appear over and over again in various forms of cancer will help us design new and better interventions," says Croce.

MiRNAs can behave like oncogenes, which promote tumor growth, or tumor suppressors, which keep potentially malignant cells in check. Croce points out that miRNA activity is tissue-sensitive, meaning some miRNAs may be overexpressed, or "turned on" in some of the cancers while in others they are underexpressed, or "turned off."

In the six types of cancer in the study, the majority (26) of the miRNAs were overexpressed, while 17 were underexpressed.

Calin and Volinia also identified several key cancer genes the miRNA signature targets, including the tumor suppressors retinoblastoma-1 (RB1) and transforming growth factor, beta receptor 2 (TGFBR2).

Croce predicts that miRNAs themselves may one day be used as treatments. "If we can replace miRNAs that are lost and block those that are overly abundant, then maybe we can prevent some of the very earliest changes that happen in the development of cancer. There is a lot of work that still needs to be done, but I am convinced that this field will give us more precise and less toxic ways of dealing with cancer than we have today - even considering some of our new, molecularly-targeted therapies." Support from the research came from the National Cancer Institute, the Italian Ministry of Public Health, the Italian Ministry of University Research Telethon, the Italian Association for Cancer Research and a Kimmel Scholar award to George Calin.