Gender Differences in UVB-Induced Skin Carcinogenesis, Inflammation, and DNA Damage

Thomas‐Ahner, Jennifer M.; Wulff, Brian C.; Tober, Kathleen L.; Kusewitt, Donna F.; Riggenbach, Judy; Oberyszyn, Tatiana M.

doi:10.1158/0008-5472.can-06-3798

Cited by 133 publications

(147 citation statements)

References 38 publications

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“…Similarly acute UVB treatment (0.224 J/cm 2 ) of female SKH-1 mice induced a significant increase in skin MPO activity 48 h after exposure. However, in male mice a minimal change in MPO activity was found 42 and suggests that the effect is gender-dependent. On the other hand following UVA irradiation we found no significant effect on MPO activity.…”

Section: Discussionmentioning

confidence: 93%

Differential modulation of inflammatory markers in plasma and skin after single exposures to UVA or UVB radiation in vivo

Vostalová¹,

Svobodová²,

Galandáková³

et al. 2013

BIOMED PAP

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Background. Solar light generates inflammatory responses in exposed skin. These effects are generally attributed to UVB light. However, skin is exposed to a huge quantum of UVA photons as UVA is a predominant part of sunlight and the radiation used in tanning beds. We examined the effects of a single exposure to UVA and UVB wavebands on cytokine levels in skin and plasma, myeloperoxidase (MPO) activity, expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) in skin. Methods. Hairless mice were irradiated with either UVA (10 or 20 J/cm 2 ) or UVB (200 or 800 mJ/cm 2 ). The effects were assessed after 4/24 h. Plasma cytokine levels were evaluated using a Bio-Plex cytokine assay. Cytokine, iNOS and COX-2 levels in skin were determined by Western blot. Skin MPO activity was monitored spectrophotometrically. Results. UVB induced up-regulation of interleukin-1β (IL-1β) and interleukin-6 (IL-6) and decrease in interleukin-10 (IL-10) mainly after 4 h. In contrast, UVA caused increase in levels of tumor necrosis factor-alpha (TNF-α) and IL-6 after 4 h and up-regulated IL-10 and interleukin-12 (IL-12) after 24 h. The increase in MPO activity from infiltrated leucocytes was observed only in UVB irradiated animals. iNOS was up-regulated 4 h after UVA and UVB treatment. No significant effect on COX-2 expression was detected. Conclusions. UVA and UVB light affected several inflammatory markers. For individual waveband, changes in plasma parameters did not correlate with those in skin. Thus evaluation of plasma samples cannot simply be replaced by determination in skin specimens and vice versa.

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Section: Discussionmentioning

confidence: 93%

Differential modulation of inflammatory markers in plasma and skin after single exposures to UVA or UVB radiation in vivo

Vostalová¹,

Svobodová²,

Galandáková³

et al. 2013

BIOMED PAP

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“…H&E-stained sections of tumors/lesions were graded in a blinded manner as reported previously (29,36). A Nikon Eclipse 80i microscope with Surveyor Mosaic Imaging system at the UNC Neuroscience Confocal and Multi Photon Imaging Facility was used to grade the tumors.…”

Section: Methodsmentioning

confidence: 99%

Control of skin cancer by the circadian rhythm

Gaddameedhi

Selby²,

Kaufmann

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

199

266

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Skin cancer is the most common form of cancer in the United States. The main cause of this cancer is DNA damage induced by the UV component of sunlight. In humans and mice, UV damage is removed by the nucleotide excision repair system. Here, we report that a rate-limiting subunit of excision repair, the xeroderma pigmentosum group A (XPA) protein, and the excision repair rate exhibit daily rhythmicity in mouse skin, with a minimum in the morning and a maximum in the afternoon/evening. In parallel with the rhythmicity of repair rate, we find that mice exposed to UV radiation (UVR) at 4:00 AM display a decreased latency and about a fivefold increased multiplicity of skin cancer (invasive squamous cell carcinoma) than mice exposed to UVR at 4:00 PM. We conclude that time of day of exposure to UVR is a contributing factor to its carcinogenicity in mice, and possibly in humans.circadian clock | cryptochrome | sunbathing | tanning salons S kin cancer is the most common form of cancer in the United States. With over 1.3 million new cases each year, it constitutes nearly 40% of all diagnosed cancers (1). Moreover, because of changes in lifestyle and the environment, the incidence of skin cancer is steadily increasing (2). The main causative agent of skin cancer is the UV component of sunlight. UV radiation (UVR) produces two major lesions in DNA, the cyclobutane pyrimidine dimer (CPD) and the (6-4) photoproduct [(6-4) PP], both of which are mutagenic and carcinogenic in animal model systems and are thought to be the primary cause of skin cancer in humans (3-7).In mice and humans, nucleotide excision repair is the sole repair system for removing CPDs and (6-4) PPs from DNA. As a consequence, humans with hereditary mutations in excision repair genes suffer from xeroderma pigmentosum, a syndrome characterized by a nearly 5,000-fold increase in skin cancer in sunlight-exposed areas of the afflicted individuals (8). Excision repair involves photoproduct removal by dual incisions bracketing the lesion, removal of the damage in the form of a 24-to 32-nt-long oligomer, filling in the resulting single-stranded gap, and sealing by ligase (9). The dual incision is carried out by six excision repair factors: RPA, xeroderma pigmentosum group A (XPA), XPC, TFIIH, XPG, and XPF-ERCC1 (10). Recently, in a study that analyzed liver and brain tissues from mice, it was found that XPA, a critical protein involved in damage recognition and a rate-limiting factor in excision repair, is controlled by the core molecular circadian clock (11, 12). As a consequence, excision repair activity exhibited circadian rhythmicity in these organs, increasing during the day to reach a maximum at 4-6:00 PM and decreasing during the night to a minimum at 4-6:00 AM.Here we analyzed the expression pattern of XPA and excision repair activity in mouse skin. We found that protein and repair activity exhibit a circadian rhythm similar to that found in the liver and brain. To determine whether this rhythmicity affected UV-induced skin cancer development we exposed a...

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“…Based on previous studies of skin cancer induction and Zn supplementation, 8‐hydroxy‐2′ ‐deoxyguanosine (8‐OHdG), and γ H2AX were chosen for expression analysis in the various treatment groups 14, 27. Antisera used are listed in Table 1, with antigen retrieval and detection methods.…”

Section: Methodsmentioning

confidence: 99%

Reduction in squamous cell carcinomas in mouse skin by dietary zinc supplementation

Sun

Shen²,

Schrock

et al. 2016

Cancer Medicine

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Inadequate dietary Zn consumption increases susceptibility to esophageal and other cancers in humans and model organisms. Since Zn supplementation can prevent cancers in rodent squamous cell carcinoma (SCC) models, we were interested in determining if it could have a preventive effect in a rodent skin cancer model, as a preclinical basis for considering a role for Zn in prevention of human nonmelanoma skin cancers, the most frequent cancers in humans. We used the 7,12‐dimethyl benzanthracene carcinogen/phorbol myristate acetate tumor promoter treatment method to induce skin tumors in Zn‐sufficient wild‐type and Fhit (human or mouse protein) knockout mice. Fhit protein expression is lost in >50% of human cancers, including skin SCCs, and Fhit‐deficient mice show increased sensitivity to carcinogen induction of tumors. We hypothesized that: (1) the skin cancer burdens would be reduced by Zn supplementation; (2) Fhit −/−(Fhit, murine fragile histidine triad gene) mice would show increased susceptibility to skin tumor induction versus wild‐type mice. 30 weeks after initiating treatment, the tumor burden was increased ~2‐fold in Fhit −/− versus wild‐type mice (16.2 versus 7.6 tumors, P < 0.001); Zn supplementation significantly reduced tumor burdens in Fhit −/− mice (males and females combined, 16.2 unsupplemented versus 10.3 supplemented, P = 0.001). Most importantly, the SCC burden was reduced after Zn supplementation in both strains and genders of mice, most significantly in the wild‐type males (P = 0.035). Although the mechanism(s) of action of Zn supplementation in skin tumor prevention is not known in detail, the Zn‐supplemented tumors showed evidence of reduced DNA damage and some cohorts showed reduced inflammation scores. The results suggest that mild Zn supplementation should be tested for prevention of skin cancer in high‐risk human cohorts.

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Gender Differences in UVB-Induced Skin Carcinogenesis, Inflammation, and DNA Damage

Cited by 133 publications

References 38 publications

Differential modulation of inflammatory markers in plasma and skin after single exposures to UVA or UVB radiation in vivo

Differential modulation of inflammatory markers in plasma and skin after single exposures to UVA or UVB radiation in vivo

Control of skin cancer by the circadian rhythm

Reduction in squamous cell carcinomas in mouse skin by dietary zinc supplementation

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