Aug. 15, 2011 Researchers at the University of Pittsburgh Cancer Institute (UPCI) have identified the oncoprotein that allows a common and usually harmless virus to transform healthy cells into a rare but deadly skin cancer called Merkel Cell Carcinoma (MCC). Their findings, published August 15 in the Journal of Clinical Investigation, could improve diagnosis for MCC and may help in understanding how other cancers arise.
Three years ago, Yuan Chang, M.D., and Patrick S. Moore, M.D., M.P.H., in the Cancer Virology Program at UPCI, discovered a new human cancer virus, called Merkel Cell polyomavirus (MCV), that causes most cases of MCC. But until now, it was not clear how the virus triggered cancer development.
To figure that out, lead author Masahiro Shuda, Ph.D., UPCI research associate, and the team systematically examined the viral proteins that might trigger cancer cell growth. After establishing human MCC cell lines, the scientists learned that knocking out a viral protein called "small tumor protein," or sT, stopped the cancer cells from replicating. When they introduced sT into healthy cells in the lab, the cells took on the characteristics of cancer cells.
"This was a surprise because the viral sT proteins from other similar viruses that cause cancers in laboratory animals do not directly increase cancer activity in cells," Dr. Shuda said. "Once we found this, we had to next understand the biological mechanisms that make MCV sT a cancer-causing protein, or oncoprotein."
The MCV sT triggers a cellular process called "cap-dependent translation" that allows certain cellular oncoproteins to be made, Dr. Moore explained. Although the cancers caused by MCV are rare, the virus is important because it helps scientists pinpoint cell pathways that are key to more common cancers. These cancers also might activate cap-dependent translation through a DNA mutation rather than through a virus infection.
In related studies recently published by the team in Emerging Infectious Diseases, MCV was shown to normally infect four out of five healthy adults, where it remains a silent resident in skin cells without causing any symptoms. Only when specific mutations occur in the DNA of the virus―for example, by ultraviolet light exposure―does it have potential to cause cancer. The researchers are now working to identify new agents to target MCC cancer cells that may be more active and less toxic.
MCV is the first virus in the family of polyomaviruses shown to cause human cancer, but six other polyomaviruses have recently been discovered as inapparent infections of people, and scientists are actively seeking to find out if they are additional, cancer-causing viruses as well. MCV is the second human cancer virus found by the Chang-Moore laboratory, which previously also discovered the virus causing Kaposi's sarcoma -- the most common cancer among AIDS patients.
Other co-authors are Hyun Jin Kwun, Ph.D., and Huichen Fung, Ph.D., both of the Cancer Virology Program. The research was funded by the National Institutes of Health, the American Cancer Society and UPCI. Dr. Chang is an American Cancer Society Professor of pathology, and Dr. Moore is an American Cancer Society Professor of microbiology and molecular genetics, Pitt School of Medicine.
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