title: Malondialdehyde-derived epitopes in human skin result from acute exposure to solar UV and occur in nonmelanoma skin cancer tissue.
abstract: Cutaneous exposure to solar ultraviolet radiation (UVR) is a causative factor in photoaging and photocarcinogenesis. In human skin, oxidative stress is widely considered a key mechanism underlying the detrimental effects of acute and chronic UVR exposure. The lipid peroxidation product malondialdehyde (MDA) accumulates in tissue under conditions of increased oxidative stress, and the occurrence of MDA-derived protein epitopes, including dihydropyridine-lysine (DHP), has recently been substantiated in human skin. Here we demonstrate for the first time that acute exposure to sub-apoptogenic doses of solar simulated UV light (SSL) causes the formation of free MDA and protein-bound MDA-derived epitopes in cultured human HaCaT keratinocytes and healthy human skin. Immunohistochemical staining revealed that acute exposure to SSL is sufficient to cause an almost twenty-fold increase in general MDA- and specific DHP-epitope content in human skin. When compared to dose-matched solar simulated UVA, complete SSL was more efficient generating both free MDA and MDA-derived epitopes. Subsequent tissue microarray (TMA) analysis revealed the prevalence of MDA- and DHP-epitopes in nonmelanoma skin cancer (NMSC). In squamous cell carcinoma tissue, both MDA- and DHP-epitopes were increased more than threefold as compared to adjacent normal tissue. Taken together, these date demonstrate the occurrence of MDA-derived epitopes in both solar UVR-exposed healthy human skin and NMSC TMA tissue; however, the potential utility of these epitopes as novel biomarkers of cutaneous photodamage and a functional role in the process of skin photocarcinogenesis remain to be explored.
authors.affiliation: The University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA; Department of Biomedical Engineering, College of Engineering, University of Arizona, Tucson, AZ, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Williams
authors.affiliation: The University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA; Department of Medicine, University of Arizona, Tucson, AZ, USA.
authors.forename: Yira
authors.initials: Y
authors.lastname: Bermudez
authors.affiliation: The University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA; Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, USA.
authors.forename: Sophia L
authors.initials: SL
authors.lastname: Park
authors.affiliation: The University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA; Department of Medicine, University of Arizona, Tucson, AZ, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Stratton
authors.affiliation: Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Uchida
authors.affiliation: Department of Surgery, College of Medicine, University of Arizona, Tucson, AZ, USA.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Hurst
authors.affiliation: The University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA; Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, USA. Electronic address: wondrak@pharmacy.arizona.edu.
authors.forename: Georg T
authors.initials: GT
authors.lastname: Wondrak
mesh_terms: D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004095:Dihydropyridines / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology; D000939:Epitopes / Q000737:chemistry / Q000276:immunology*; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D008315:Malondialdehyde / Q000032:analysis / Q000737:chemistry* / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000528:radiation effects; D011506:Proteins / Q000737:chemistry; D012867:Skin / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects; D046888:Tissue Array Analysis; D014466:Ultraviolet Rays
chemical_list: D004095:Dihydropyridines; D000939:Epitopes; D011506:Proteins; D008315:Malondialdehyde
keywords: DHP-lysine; Lipid peroxidation; Malondialdehyde; Nonmelanoma skin cancer; Photocarcinogenesis; Photodamage