Microchip to track genetic signature of cancer and normal tissue

Jun 23 2004

MicroRNAs (miRNAs), tiny pieces of genetic material that can serve as stop signs for gene expression and protein synthesis, are thought to be important in the development of cancer.

Now, researchers at Jefferson Medical College and the Kimmel Cancer Center of Thomas Jefferson University in Philadelphia have developed a technique that allows them to find which miRNA genes are expressed – and how – in both cancerous and normal tissue.

Scientists, led by Carlo Croce, M.D., director of Jefferson’s Kimmel Cancer Center and professor of microbiology and immunology at Jefferson Medical College, have developed a microarray chip onto which they were able to put all the known miRNA genes in both human and mouse. They found that each tissue they tested had its own characteristic pattern of miRNA gene expression.

The work might enable scientists to gain a better understanding of the roles of miRNAs in cancer and provide targets for future drug development. They reported their findings June 21, 2004 online in the Proceedings of the National Academy of Sciences.

Dr. Croce explains that miRNAs are thought to play important roles in regulating gene expression during development and cell differentiation. MiRNAs inhibit the function of their targets, typically messenger RNA, which is involved in gene expression. They either degrade the messenger RNA or block its translation. Cells in organisms from yeast to mammals make interfering RNA to shut off gene expression in development.

Dr. Croce and his colleagues had previously shown that deletions in miRNA genes were involved in B-cell chronic lymphocytic leukemia (CLL), the most common adult leukemia in the Western world. They also had reported that human miRNA genes are frequently located in “fragile” areas of the genome that are vulnerable to mutation. “We think the miRNA genes are in fact involved in many human cancers,” he says.

“As a result, we have a number of markers that allow us to characterize specific tissue in specific cells,” Dr. Croce says. “Now the chip allows us to compare normal tissue to malignant tissue.

“This kind of approach will give us important clues about the gene regulation in a number of cells in normal and cancer tissue,” he says. “It opens new avenues for treatment because these miRNA genes are so small, they can get into cells and be used as drugs. Characterizing their targets might help in understanding cancer phenotypes.”

MiRNA genes can function differently. Take miR-16, for example, which is one of the miRNA genes Dr. Croce has studied in CLL. It functions as a tumor suppressor, and probably some of its targets are oncogenes, he says. Tumor suppressor genes are normal genes that protect against the development of cancer. Oncogenes, on the other hand, promote excessive cell growth, the hallmark of cancer.

“If the miR is expressed at a high level, however, the RNA level of the targets would be low and the expression of the oncogene would be low,” he says. Conversely, “knocking out” the miR gene would mean the expression of the oncogene would be high.

“MiRNAs are a new mechanism involved in malignant transformation,” he says. “I think it will be found to be a very generalized mechanism and provide a lot of opportunities for treatment.

“The chip is an easy way to test for miRNA alterations,” he says. “When you look at a cancer, the chip will tell you which miRNAs are in fact there and which are not. Then you can study the targets and figure out their role in cancer.

“The next step is to continue to find out how these genes are regulated and what they regulate – their targets and their roles in cancers.”

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