MiRNA is opening up a whole new way of understanding carcinogenesis

Aug 15 2005

Scientists mining vast, largely unexplored regions of the human genome have identified a small handful of mini-molecules that play a major role in the development of cancer and perhaps many other diseases.

This newly identified set of molecules is called microRNA (miRNA), a collection of hundreds of snippets of non-coding RNA - typically no more than 22 nucleotides in length - that may comprise a master network controlling genes and protein production throughout the body, according to scientists in Ohio State University's Comprehensive Cancer Center.

The researchers were the first to define how miRNA malfunctions in some forms of leukemia and lymphoma, and now have discovered how it works in breast cancer. More importantly, they say the miRNA "signature" in breast cancer is directly linked to several biological features that physicians routinely use to diagnose and appropriately treat the disease.

The findings appear in the Aug. 15 issue of Cancer Research.

"MiRNA is opening up a whole new way of understanding carcinogenesis," says Carlo Croce, professor and chair of the department of molecular virology, immunology and medical genetics at Ohio State and the senior author of the study.

Traditional science holds that a specific stretch of DNA, or gene, encodes a sequence of messenger RNA that in turn creates instructions for the cell to make a particular protein. Cancer arises when there are mutations, deletions or other alterations in that initiating gene.

But what governs the entire process? A growing number of researchers like Croce believe that miRNA may play a major role. In contrast to regular RNA, miRNA does not code for protein production. Instead, it causes the destruction of coding RNA directly, or garbles its translational activity so proper protein production cannot take place.

MiRNA was first discovered almost 15 years ago in studies of roundworms, and since then, it has been found throughout plant and animal genomes. Because it becomes active early on in development and appears to be tissue-specific, researchers believe miRNA plays a fundamental role throughout an organism's lifespan.

Scientists have identified over 200 distinct miRNAs, but Croce feels there may be hundreds more, and adds that researchers are just beginning to understand what they do. "Some of the breast cancer-specific miRNA we identified appear to act like tumor suppressors, and others appear to act like oncogenes, encouraging tumor growth."

Interestingly, earlier research in Croce's laboratory revealed that the majority of miRNA genes in humans are located near chromosomal sites that are especially vulnerable to alteration, a finding that leads him to believe that the role of miRNA in cancer is underestimated.

Croce, along with colleagues at Ohio State, Thomas Jefferson University and three cancer centers in Italy, used a microarray containing all known miRNA to examine miRNA activity in 76 breast tumors. They compared the findings to a microarray analysis of 34 samples of normal breast tissue.

They found 29 miRNAs that are significantly deregulated in breast cancer (some were over-expressed and others were under-expressed) and discovered that only five members of that group (identified as miR10b, miR-125b, miR-145, miR-21 and miR-155) were needed to successfully separate normal tissue from cancerous tissue 100 percent of the time.

They also conducted multiple tests designed to reveal any links between the newly identified expression pattern and important clinical features of the breast cancer, such as the type of the cancer - lobular versus ductal, estrogen and progesterone receptor status, lymph node metastasis, vascular invasion, proliferation index, and presence of two genes that can play a role in tumor growth, HER2 and p53.

They found that miRNA expression was correlated with breast tumors' hormone status as well as its metastatic, invasive and proliferative potential.

"This leaves little doubt that aberrant expression of miRNA is involved in the development of breast cancer," says Croce, adding that this information and the results of related studies already under way should offer valuable information for physicians as well as for researchers designing new treatments.