Study may help explain sunlight’s role in melanoma development, have screening implications
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 that ultraviolet light exposure accelerated melanoma formation on the treated mice compared with melanomas arising spontaneously in the absence of such exposure. The researchers found targeting of the Rb pathway, either by an increase in CDK6 expression or a loss of p16INK4a, in the melanomas that developed on mice treated with a single exposure of ultraviolet light - essentially, a mouse sunburn. In mice genetically engineered to lack p16INK4a, however, ultraviolet light exposure did not increase melanoma formation.
"These data suggest that it is not so much this gene or that gene, but the pathway that is what UV light targets," Sharpless said.
"This is one of the better mouse models for any human tumor that I’m aware of," he added. "This finding is unique in that it identifies the Rb pathway as a target of UV’s mutagenic action."
The next research step is to look at a collection of clinical samples to determine if exclusive lesions in the Rb pathway are linked to melanomas from patients with a detailed history of ultraviolet light exposure.
"Melanoma screening is a good idea, but it needs some molecular help to distinguish the really high-risk patients from those at a lower risk for developing melanoma," Sharpless said. "This would be a way to deal with this very large clinically heterogeneous population of patients at risk."
The Howard Hughes Medical Institute and the National Institutes of Health provided funding for the research.
By Kerilyn R. Wick
UNC School of Medicine
Note: Contact Sharpless at (919) 966-1185 or email@example.com
School of Medicine contact: Les Lang, (919) 843-9687 or firstname.lastname@example.org
Leslie Lang | EurekAlert!