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Study may help explain sunlight's role in melanoma development, have screening implications

CHAPEL HILL -- A strong link exists between lifetime exposure to ultraviolet light, particularly lifetime sunburns, and the development of melanoma - the most lethal form of skin cancer.

Now, for the first time, scientists have identified a specific molecular pathway within cells that becomes mutated by ultraviolet light exposure, thereby speeding up melanoma development.

New findings published in the Feb. 4 issue of Proceedings of the National Academy of Sciences may have implications for screening people at high risk, including those "with a significant history of sunburn and suspicious skin moles," said study co-author, Dr. Norman Sharpless, assistant professor of medicine and genetics at the University of North Carolina at Chapel Hill School of Medicine and a member of UNC's Lineberger Comprehensive Cancer Center.

"Who hasn't been sunburned?" he said. "This work suggests a rational method for risk stratification, for screening questionable skin moles - atypical nevi - for specific molecular lesions."

In the new study, Sharpless and colleagues at Harvard Medical School used mice deficient in an important tumor suppressor protein connected to the "anti-cancer" cell signaling pathway ARF-p53. In addition to this deficiency, these mice were genetically designed to produce another protein, H-Ras, in their pigmented skin cells, or melanocytes.

"Loss of ARF-p53 and activation of Ras are two of three hallmark events detected in human melanomas. The third being loss in another 'anti-cancer' cell signaling pathway, p16INK4a-Rb," said Sharpless.

This mouse model allowed researchers to selectively test the effects of ultraviolet light exposure on the p16INK4a-Rb pathway.

The Rb pathway regulates cell growth. The retinoblastoma protein acts to hold cell proliferation in check. The regulatory capacity of Rb is moderated by CDK6 and the tumor suppressor protein, p16INK4a.

In this work, the authors showed t
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Contact: Leslie Lang
llang@med.unc.edu
919-843-9687
University of North Carolina School of Medicine
21-Feb-2003


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