8-hydroxyguanine and Skin-Neoplasms

UV-induced DNA damage plays a key role in the initiation phase of skin cancer. When left unrepaired or when damaged cells are not eliminated by apoptosis, DNA lesions express their mutagneic properties, leading to the activation of proto-oncogene or the inactivation of tumor suppression genes. The chemical nature and the amount of DNA damage strongly depend on the wavelength of the incident photons. The most energetic part of the solar spectrum at the Earth's surface (UVB, 280-320 nm) leads to the formation of cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts (64PPs). Less energetic but 20-times more intense UVA (320-400 nm) also induces the formation of CPDs together with a wide variety of oxidatively generated lesions such as single strand breaks and oxidized bases. Among those, 8-oxo-7,8-dihydroguanine (8-oxoGua) is the most frequent since it can be produced by several mechanisms. Data available on the respective yield of DNA photoproducts in cells and skin show that exposure to sunlight mostly induces pyrimidine dimers, which explains the mutational signature found in skin tumors, with lower amounts of 8-oxoGua and strand breaks. The present review aims at describing the basic photochemistry of DNA and discussing the quantitative formation of the different UV-induced DNA lesions reported in the literature. Additional information on mutagenesis, repair and photoprotection is briefly provided.

Topics: Animals; DNA Adducts; DNA Damage; DNA Repair; Guanine; Humans; Melanins; Proto-Oncogene Mas; Pyrimidine Dimers; Skin Neoplasms; Ultraviolet Rays

Reactive oxygen species (ROS) are associated not only with initiation, but also with promotion and progression in the multistage carcinogenesis model. In the present review, we will focus on the involvement of ROS in skin carcinogenesis, especially that induced by ultraviolet (UV) radiation. UV-specific DNA damage has been well studied thus far. However, recent reports have revealed the previously unknown participation of oxidative stress in UV-induced skin carcinogenesis. Indeed, in addition to transition-type mutations at dipyrimidine sites, G:C to T:A transversions, which may be induced by the presence of 8-oxoguanine during DNA replication, are frequently observed in the ras oncogene and p53 tumor suppressor gene in human skin cancers of sun-exposed areas and in UV-induced mouse skin cancers. Recent studies have shown that not only UV-B, but also UV-A is involved in UV-induced carcinogenesis. A wide variety of biological phenomena other than direct influence by UV, such as inflammatory and immunological responses and oxidative modifications of DNA and proteins, appear to play roles in UV-induced skin carcinogenesis. Furthermore, it has become clear that genetic diseases such as xeroderma pigmentosum show deficient repair of oxidatively modified DNA lesions. The involvement of ROS in skin carcinogeneisis caused by arsenic and chemical carcinogens will also be discussed.

Topics: Animals; DNA; DNA Damage; Genes, p53; Guanine; Humans; Mice; Models, Biological; Mutation; Neoplasms, Radiation-Induced; Reactive Oxygen Species; Skin Neoplasms; Ultraviolet Rays

Oxidative stress plays a role in UV-induced melanoma, which may arise from melanocytic nevi. We investigated whether oral administration of the antioxidant N-acetylcysteine (NAC) could protect nevi from oxidative stress in vivo in the setting of acute UV exposure. The minimal erythemal dose (MED) was determined for 100 patients at increased risk for melanoma. Patients were randomized to receive a single dose (1,200 mg) of NAC or placebo, in double-blind fashion, and then one nevus was irradiated (1-2 MED) using a solar simulator. One day later, the MED was redetermined and the irradiated nevus and a control unirradiated nevus were removed for histologic analysis and examination of biomarkers of NAC metabolism and UV-induced oxidative stress. Increased expression of 8-oxoguanine, thioredoxin reductase-1, and γ-glutamylcysteine synthase modifier subunit were consistently seen in UV-treated compared with unirradiated nevi. However, no significant differences were observed in these UV-induced changes or in the pre- and postintervention MED between those patients receiving NAC versus placebo. Similarly, no significant differences were observed in UV-induced changes between subjects with germline wild-type versus loss-of-function mutations in the melanocortin-1 receptor. Nevi showed similar changes of UV-induced oxidative stress in an open-label post-trial study in 10 patients who received NAC 3 hours before nevus irradiation. Thus, a single oral dose of NAC did not effectively protect nevi from UV-induced oxidative stress under the conditions examined. Cancer Prev Res; 10(1); 36-44. ©2016 AACR.

Topics: Acetylcysteine; Administration, Oral; Antioxidants; Biomarkers; Double-Blind Method; Glutamate-Cysteine Ligase; Guanine; Humans; Melanoma; Mutation; Nevus, Pigmented; Oxidative Stress; Pilot Projects; Receptor, Melanocortin, Type 1; Skin Neoplasms; Sunlight; Thioredoxin Reductase 1; Ultraviolet Rays

Basal cell carcinoma (BCC) is the most common type of skin cancer and is a major public health problem in many Western countries. It usually occurs as a consequence of exposure to ultraviolet radiation (UV) with sunlight. The DNA photolesion 8-oxo-7,8-dihydroguanine (8-oxo-dG) is caused by reactive oxygen species (ROS) produced in response to UVA, UVB, and oxidative metabolism. If this damaged DNA is not repaired prior to cell division, then gene mutations may persist in daughter cells. Human 8-oxoguanine-DNA glycosylase 1 (hOGG1) is the main enzyme that excises 8-oxo-dG from damaged DNA via the base-excision repair pathway. However, the role of hOGG1 in human skin cancer is unknown. In this study, using immunohistochemical staining, we found low hOGG1 protein expression in human BCC compared to overlying epidermis or normal epidermis. We also found higher levels of 8-oxo-dG within the BCC compared to the basal layers of epidermis overlying the BCC lesions (E-BCC). The results suggest that low expression of hOGG1 within BCC results in accumulation of ROS generated 8-oxo-dG due to low levels of DNA repair, thereby implicating hOGG1 in human BCC carcinogenesis. These ROS are likely to be produced by the cancer cells during metabolism, as the BCC nests are too deep for UV to reach. Our data suggests that procedures that increase expression of hOGG1 within BCC, or protect from ROS may be beneficial for reducing progression of BCC.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Basal Cell; DNA Glycosylases; DNA Repair; Epidermal Cells; Epidermis; Female; Gene Expression Regulation, Neoplastic; Guanine; Humans; Male; Middle Aged; Reactive Oxygen Species; Skin Neoplasms

Excessive exposure to UV radiation is a major risk factor for developing skin cancer. UV-induced reactive oxygen species (ROS) cause accumulation of DNA damage products such as 8-oxoguanine (8-oxoG) in the skin. We have previously shown that mice lacking the repair enzyme 8-oxoguanine glycosylase (Ogg1 knockout mice) are highly susceptible to skin cancer after long-term UVB exposure. To investigate the genes involved, we performed gene profiling of Ogg1 knockout mouse skin after UVB exposure. Among the up-regulated genes in UVB-treated Ogg1 knockout mice, inflammatory response pathway-related genes were most affected. The Vcan gene, which encodes the large extracellular matrix proteoglycan versican, was continuously up-regulated in UVB-treated Ogg1 knockout mice, suggesting that versican is a mediator of skin cancer development. We examined the expression pattern of versican in skin tumors from wild-type mice and UVB-treated Ogg1 knockout mice, and also analyzed 157 sun-related human skin tumors. Versican was strongly expressed in malignant skin tumors in both mice and humans, and especially in Ogg1 knockout mice. Additionally, infiltrating neutrophils strongly colocalized with versican in UVB-treated Ogg1 knockout mouse skin. These data demonstrate that inflammatory responses, particularly neutrophil infiltration and versican up-regulation, are closely involved in UVB/ROS-induced skin tumorigenesis.

Topics: Animals; Cell Transformation, Neoplastic; Dermatitis; DNA Damage; DNA Glycosylases; Down-Regulation; Gene Expression Profiling; Guanine; Humans; Immunohistochemistry; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophil Infiltration; Reactive Oxygen Species; Real-Time Polymerase Chain Reaction; Skin; Skin Neoplasms; Ultraviolet Rays; Up-Regulation; Versicans

Xeroderma pigmentosum (XP) C is involved in the recognition of a variety of bulky DNA-distorting lesions in nucleotide excision repair. Here, we show that XPC plays an unexpected and multifaceted role in cell protection from oxidative DNA damage. XP-C primary keratinocytes and fibroblasts are hypersensitive to the killing effects of DNA-oxidizing agents and this effect is reverted by expression of wild-type XPC. Upon oxidant exposure, XP-C primary keratinocytes and fibroblasts accumulate 8,5'-cyclopurine 2'-deoxynucleosides in their DNA, indicating that XPC is involved in their removal. In the absence of XPC, a decrease in the repair rate of 8-hydroxyguanine (8-OH-Gua) is also observed. We demonstrate that XPC-HR23B complex acts as cofactor in base excision repair of 8-OH-Gua, by stimulating the activity of its specific DNA glycosylase OGG1. In vitro experiments suggest that the mechanism involved is a combination of increased loading and turnover of OGG1 by XPC-HR23B complex. The accumulation of endogenous oxidative DNA damage might contribute to increased skin cancer risk and account for internal cancers reported for XP-C patients.

Topics: Bromates; Cells, Cultured; DNA Damage; DNA Glycosylases; DNA Repair; DNA Repair Enzymes; DNA-Binding Proteins; Guanine; Humans; Keratinocytes; Oxidants; Skin Neoplasms; X-Rays; Xeroderma Pigmentosum

8-Oxoguanine is one of the oxidative DNA damages that can result in stable mutations. The Ogg1 gene encodes the repair enzyme 8-oxoguanine-DNA glycosylase, which removes the oxidized base from DNA. In this study, we investigated the role of 8-oxoguanine in skin carcinogenesis induced by UVB irradiation using Ogg1 knockout mice (C57Bl/6J background). We examined the effect of UVB irradiation on the formation of 8-oxoguanine in epidermal cells using immunostaining and found that the level of 8-oxoguanine in Ogg1 knockout mice 24 hours after UVB irradiation remained high compared with that in wild-type and heterozygous mice. To verify the effect of chronic UVB irradiation on 8-oxoguanine formations in epidermal cells, we irradiated wild-type, heterozygous, and Ogg1 knockout mice with UVB at a dose of 2.5 kJ/m2 thrice a week for 40 weeks. We found that the mean number of tumors in Ogg1 knockout mice was 3.71, which was significantly more than in wild-type and heterozygous mice, being 1.71 and 2.28, respectively. The rate of developing malignant tumors in Ogg1 knockout mice was also significantly higher (88.5%; squamous cell carcinomas, 73.1%; sarcomas, 15.4%) than in wild-type mice (50.0%; squamous cell carcinomas, 41.7%; sarcomas, 8.3%). Moreover, the age of onset of developing skin tumors in Ogg1 knockout mice was earlier than in the other types of mice. These results clearly indicate that oxidative DNA damage induced by sunlight plays an important role in the development of skin cancers.

Topics: Animals; Cocarcinogenesis; DNA Damage; DNA Glycosylases; Female; Genetic Predisposition to Disease; Guanine; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Oxidation-Reduction; Skin Neoplasms; Ultraviolet Rays

UVA (320-400 nm) radiation constitutes >90% of the environmentally relevant solar UV radiation, and it has been proposed to have a role in skin cancer and aging. Because of the popularity of UVA tanning beds and prolonged periods of sunbathing, the potential deleterious effect of UVA has emerged as a source of concern for public health. Although generally accepted, the impact of DNA damage on the cytotoxic, mutagenic, and carcinogenic effect of UVA radiation remains unclear. In the present study, we investigated the sensitivity of a panel of yeast mutants affected in the processing of DNA damage to the lethal and mutagenic effect of UVA radiation. The data show that none of the major DNA repair pathways, such as base excision repair, nucleotide excision repair, homologous recombination, and postreplication repair, efficiently protect yeast from the lethal action of UVA radiation. In contrast, the results show that the Ogg1 DNA glycosylase efficiently prevents UVA-induced mutagenesis, suggesting the formation of oxidized guanine residues. Furthermore, sequence analysis of UVA-induced canavanine-resistant mutations reveals a bias in favor of GC-->TA events when compared with spontaneous or H(2)O(2)-, UVC-, and gamma-ray- induced canavanine-resistant mutations in the WT strain. Taken together, our data point out a major role of oxidative DNA damage, mostly 7,8-dihydro-8-oxoguanine, in the genotoxicity of UVA radiation in the yeast Saccharomyces cerevisiae. Therefore, the capacity of skin cells to repair 7,8-dihydro-8-oxoguanine may be a key parameter in the mutagenic and carcinogenic effect of UVA radiation in humans.

Topics: Aging; Canavanine; DNA Damage; DNA Glycosylases; DNA Repair; Drug Resistance, Fungal; Gamma Rays; Guanine; Humans; Mutagenesis; Mutation; Oxidation-Reduction; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Skin; Skin Neoplasms; Ultraviolet Rays