University of Florida researchers have identified specific human genes targeted by a virus believed to cause Kaposi's sarcoma, a rare form of cancer associated with AIDS and with organ transplants that causes patches of red or purple tissue to grow under people's skin.
Writing May 11 in PLOS Pathogens, the scientists are the first to name human genes that are actually hijacked by a virus wielding minimolecules called microRNAs. Apparently the viral microRNAs silence genes known to influence growth of blood vessels and suppress tumor cells. Scientists believe that with the regulatory genes sidelined, blood vessel growth runs rampant, resulting in the typical markings of Kaposi's sarcoma.
"The hallmarks of Kaposi's sarcoma are red spots full of blood vessels on the necks, arms and legs of patients," said Rolf Renne, Ph.D., an associate professor of molecular genetics and microbiology at the College of Medicine and a member of the UF Shands Cancer Center and the UF Genetics Institute. "We think that the tumor virus is using microRNAs to make sure infected cells are well nourished and protected from the human immune system."
Thought to be little more than cellular debris less than a decade ago, microRNAs are short chemical strands that strategically silence gene activity by binding to RNA within cells. They play a role in healthy development -- no one with a complete set of fingers and toes would want their genes to keep adding new digits -- and they evidently may be involved in the onset of some diseases, including cancer.
Now it seems that even foreign microRNA has a say in human health.
In an effort to identify human gene targets, UF scientists equipped cultured human cells with just 10 genes from the Kaposi's sarcoma virus, thus endowing human cells with the ability to produce viral microRNA. Scientists then screened the more than 30,000 genes that exist within human cells and found that 81 were strongly inhibited in the presence of the viral microRNA.
Five of the most affected genes are known to suppress tumor and blood vessel growth and influence the body's immune response, suggesting that the herpesvirus uses microRNA to create a cancerous environment in which it thrives, undetected by the body's natural defenses.
Researchers confirmed the results of the microRNA gene profiling with tests to detect individual microRNA activity in specific genes. "The data beautifully showed which genes were regulated by the viral microRNA," said Henry Baker, Ph.D., a professor and interim chairman of molecular genetics and microbiology who oversaw the gene screening. "The most exciting thing was one of the most-targeted genes on the list is thrombospondin 1. When something is important in a natural process, there are often a lot of built-in redundancies. In this case all of the viral microRNAs were used to target 34 different binding sites on the human gene, so apparently this is a virus that really wants to down-regulate thrombospondin."
In some people Kaposi's sarcoma virus -- technically it's in the family of herpesviruses -- causes patches of cancerous tissue bursting with blood vessels. The disease itself is rare in the United States and usually not life threatening, classically affecting elderly men of Mediterranean or Jewish heritage. More recently it has been found in greater numbers in people with immune systems weakened by human immunodeficiency virus infection and AIDS.
At its peak, about a quarter of sexually active men with AIDS developed Kaposi's sarcoma, but that rate of occurrence dropped dramatically with more effective treatment of HIV infection, according to the American Cancer Society. In addition, the disease occurs in about one in 200 transplant patients in the United States.
Other as yet unidentified genes could be affected by the microRNA of Kaposi's sarcoma virus, according to Mark Samols, a graduate student of molecular genetics and the paper's lead author. But by knowing at least some of the major genes being targeted, scientists have a place to start as they strive to develop therapies.
"The Kaposi's sarcoma herpesvirus is a very efficient parasite," said Jae U. Jung, Ph.D., a professor of microbiology and molecular genetics at Harvard Medical School who was not involved in the research. "It needs blood vessels to get food to the cell so it can survive, but thrombospondin blocks the virus' food supply line. So the virus uses these small fragments of RNA to knock down the threat to its food supply. No one is certain of the exact function of viral microRNA and this paper shows at least one function and a cellular target. These are important findings."
The work was supported by the UF Shands Cancer Center, the Bankhead Coley Florida Medical Research Program and the National Cancer Institute.
CITATION: Samols MA, Skalsky RL, Maldonado AM, Riva A, Lopez MC, et al. (2007) Identification of cellular genes targeted by KSHV-encoded microRNAs. PLoS Pathog 3(5): e65. doi:10.1371/journal.ppat.0030065 (http://www.plospathogens.org)
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