Concordant loss of heterozygosity of DNA repair gene, <i>hOGG1</i>, in melanoma <i>in situ </i>and atypical melanocytic hyperplasia

Pashaei, Shayesteh; Liu, Liwen; Zhang, Haihong; Spencer, Horace J.; Schichman, Steven A.; Fan, Chun‐Yang; Smoller, Bruce R.

doi:10.1111/j.1600-0560.2007.00865.x

Cited by 10 publications

(4 citation statements)

References 17 publications

(16 reference statements)

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“…Several potential mechanisms of ROS accumulation in melanomas have been suggested. Loss-of-heterozygosity mutations in hOGG1, an enzyme that repairs oxidative DNA damage, have been demonstrated in a small number of melanomas 70,71 . Additionally, we have found that UVA induces Sestrin2 in melanocytes and melanoma cells, which in turn suppresses antioxidant response factor Nrf2 and increases ROS production 59 .…”

Section: Mechanisms Of Uv-induced Melanomamentioning

confidence: 99%

Mechanisms and prevention of UV‐induced melanoma

Sample

2017

Photoderm Photoimm Photomed

245

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Melanoma is the deadliest form of skin cancer and its incidence is rising, creating a costly and significant clinical problem. Exposure to ultraviolet (UV) radiation, namely UVA (315-400 nm) and UVB (280-315 nm), is a major risk factor for melanoma development. Cumulative UV radiation exposure from sunlight or tanning beds contributes to UV-induced DNA damage, oxidative stress, and inflammation in the skin. A number of factors, including hair color, skin type, genetic background, location, and history of tanning, determine the skin's response to UV radiation. In melanocytes, dysregulation of this UV radiation response can lead to melanoma. Given the complex origins of melanoma, it is difficult to develop curative therapies and universally effective preventative strategies. Here, we describe and discuss the mechanisms of UV-induced skin damage responsible for inducing melanomagenesis, and explore options for therapeutic and preventative interventions.

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Section: Mechanisms Of Uv-induced Melanomamentioning

confidence: 99%

Mechanisms and prevention of UV‐induced melanoma

Sample

2017

Photoderm Photoimm Photomed

245

224

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“…Interestingly, melanocytes isolated from melanoma patients display increased sensitivity to peroxidizing agents that correlates with endogenous antioxidant imbalance (Grammatico et al , 1998), and elevated ROS have been found in melanocytes from dysplastic nevi relative to normal skin of the same individuals (Pavel et al , 2004). In addition, mutation or loss of the enzyme hOGG-1, which repairs mutagenic oxidative DNA lesions (namely 8-oxoguanine, 8-OG), has been associated with melanoma progression (Pashaei et al , 2008; Zyrek-Betts et al , 2008). Recently, we demonstrated a role for UV-induced oxidative stress and damage in an animal model of UV-induced melanoma (Cotter et al , 2007).…”

Section: Introductionmentioning

confidence: 99%

The p16INK4A tumor suppressor regulates cellular oxidative stress

et al. 2010

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Mutations or deletions in the cyclin-dependent kinase inhibitor p16INK4A are associated with multiple cancer types, but more commonly found in melanoma tumors and associated with familial melanoma predisposition. Although p16 is thought to function as a tumor suppressor by negatively regulating the cell cycle, it remains unclear why genetic compromise of p16 predisposes to melanoma over other cancers. Here we describe a novel role for p16 in regulating oxidative stress in several cell types, including melanocytes. Expression of p16 was rapidly upregulated following UV-irradiation, and in response to H2O2-induced oxidative stress in a p38 stress-activated protein kinase-dependent manner. Knockdown of p16 using siRNA increased intracellular reactive oxygen species (ROS) and oxidative (8-oxoguanine) DNA damage which was further enhanced by H2O2 treatment. Elevated ROS were also observed in p16-depleted human keratinocytes, and in whole skin and dermal fibroblasts from Cdkn2a-deficient mice. Aberrant ROS and p38 signaling in Cdkn2a-deficient fibroblasts were normalized by expression of exogenous p16. The effect of p16 depletion on ROS was not recapitulated by knockdown of retinoblastoma protein (Rb) and did not require Rb. Finally, p16-mediated suppression of ROS could not be attributed to potential effects of p16 on cell cycle phase. These findings suggest a potential alternate Rb-independent tumor-suppressor function of p16 as an endogenous regulator of carcinogenic intracellular oxidative stress. Compared to keratinocytes and fibroblasts, we also found increased susceptibility of melanocytes to oxidative stress in the context of p16 depletion, which may explain why compromise of p16 predisposes to melanoma over other cancers.

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“…In the Xiphophorus fish model, the UV action spectrum for melanin-dependent oxidant production is identical to that for melanoma induction (20). In addition, mutation or loss of OGG-1 has been associated with melanoma progression (21, 22). Finally, we recently reported that the antioxidant N -acetylcysteine (NAC) delays tumor development in an animal model of UV-induced melanoma (23).…”

Section: Introductionmentioning

confidence: 99%

Use of OralN-Acetylcysteine for Protection of Melanocytic Nevi against UV-Induced Oxidative Stress: Towards a Novel Paradigm for Melanoma Chemoprevention

Goodson

Cotter

Cassidy

et al. 2009

Clinical Cancer Research

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Purpose: Induction of oxidative stress has been implicated in UV-induced melanoma.We sought to determine whether the antioxidant N-acetylcysteine (NAC) could be safely administered to protect melanocytic nevi from the oxidative stress resulting from acute UV exposure. Experimental Design: Patients at increased risk for melanoma were recruited from a screening clinic. Induction and detection of oxidative stress (reactive oxygen species and glutathione depletion) was optimized in nevi following ex vivo UV irradiation. Nevi were removed from patients before, and following, oral ingestion of a single (1,200 mg) dose of NAC, and then these nevi were UV irradiated (4,000 J/m 2 ). Results: Oxidative stress was induced in nevi 24 to 48 hours following ex vivo UV irradiation. A single oral dose of NAC was well tolerated in all patients (n = 72). Basal levels of reduced glutathione and the NAC metabolite cysteine were well correlated between similar-appearing nevi from the same patient and were significantly increased in nevi removed 3 hours after NAC ingestion compared with nevi removed before drug ingestion. In approximately half (9 of 19) of patients tested, UV-induced glutathione depletion was attenuated in the postdrug (compared with predrug) nevus. Conclusions: NAC can be safely administered to patients for the purpose of modulating UV-induced oxidative stress in nevi. This study suggests the feasibility of patients taking NAC prophylactically before acute UV exposure, to prevent pro-oncogenic oxidative stress in nevi and ultimately reduce long-term melanoma risk. (Clin Cancer Res 2009;15(23):7434-40) Melanoma is a potentially lethal form of skin cancer, which unfortunately in recent years has seen a dramatic increase in incidence that has not been matched by the development of effective therapies for patients with advanced disease (1). Although melanoma may arise directly from isolated melanocytes, a significant fraction of melanomas develop from nevi (or moles; ref. 2), which represent congenital or acquired clonal neoplasms of melanocytes (3). Nevi are far less prevalent on sun-protected skin and their development is related to sun exposure (4), which also is the major environmental risk factor for melanoma (5). Patients can reduce the potentially harmful effects of UV by limiting sun exposure and/or using sunscreen, although some studies suggest that sunscreen use may increase melanoma risk (6), perhaps due to increased sun exposure in sunscreen users (7). Although sunscreens are designed to prevent sunburn, it is unclear whether they protect against all possible carcinogenic effects of UV exposure. Given these considerations, and the fact that most patients do not apply sunscreens properly (8), reliance on sunscreen alone may be inadequate and there is need for additional preventive strategies.UV in sunlight is a potent inducer of reactive oxygen species (ROS) in the skin (9), which may damage intracellular constituents and deplete vital reductants such as glutathione (GSH; ref. 10). Sustained oxi...

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Concordant loss of heterozygosity of DNA repair gene, hOGG1, in melanoma in situ and atypical melanocytic hyperplasia

Abstract: These results shows that LOH at hOGG1 gene is associated with MIS and AMH and suggest that the hOGG1 gene may play a role in melanocytic tumor progression.

Cited by 10 publications

References 17 publications

Mechanisms and prevention of UV‐induced melanoma

Mechanisms and prevention of UV‐induced melanoma

The p16INK4A tumor suppressor regulates cellular oxidative stress

Use of OralN-Acetylcysteine for Protection of Melanocytic Nevi against UV-Induced Oxidative Stress: Towards a Novel Paradigm for Melanoma Chemoprevention

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