Development Of Non-melanoma Skin Cancer Research Articles

Nonneoplastic mucocutaneous lesions in organ transplant recipients

Nonneoplastic mucocutaneous lesions are frequent in organ transplant recipients. Many of them are caused by a direct toxicity of immunosuppressive drugs, in particular glucocorticoids and cyclosporine. The effects of these agents are dose- and time-dependent. Glucocorticoids can cause acne, Cushingoid appearance, irregular purpuric areas, friable skin, and wide and violaceous stripes. Cyclosporine can cause hypertrichosis, pilosebaceous lesions, and gum hypertrophy. Patients with esthetic changes may show poor adherence to treatment with these immunosuppressive agents that may lead to progressive graft dysfunction. Apart from this direct toxicity, vigorous immunosuppression may render the transplant recipients more susceptible to mucocutaneous infections. Fungal infection, viral warts, and bacterial folliculitis are the most frequent types of mucocutaneous infection. Some fungal infections, such as oral candidiasis and pityriasis versicolor, are relatively trivial, but other mycotic infections can cause severe or disfigurating lesions. Among viral infections, warts and condylomata caused by human papilloma virus are frequent and may favor the development of nonmelanoma skin cancer. Bacterial infections are usually trivial in the early period after transplantation, being represented almost exclusively by folliculitis. However, subcutaneous infections may cause a necrotizing fasciculitis which is a life-threatening disorder, usually sustained by polymicrobial pathogens.

E6 and E7 from Beta Hpv38 Cooperate with Ultraviolet Light in the Development of Actinic Keratosis-Like Lesions and Squamous Cell Carcinoma in Mice

Cutaneous beta human papillomavirus (HPV) types appear to be involved in the development of non-melanoma skin cancer (NMSC); however, it is not entirely clear whether they play a direct role. We have previously shown that E6 and E7 oncoproteins from the beta HPV type 38 display transforming activities in several experimental models. To evaluate the possible contribution of HPV38 in a proliferative tissue compartment during carcinogenesis, we generated a new transgenic mouse model (Tg) where HPV38 E6 and E7 are expressed in the undifferentiated basal layer of epithelia under the control of the Keratin 14 (K14) promoter. Viral oncogene expression led to increased cellular proliferation in the epidermis of the Tg animals in comparison to the wild-type littermates. Although no spontaneous formation of tumours was observed during the lifespan of the K14 HPV38 E6/E7-Tg mice, they were highly susceptible to 7,12-dimethylbenz(a)anthracene (DMBA)/12-0-tetradecanoylphorbol-13-acetate (TPA) two-stage chemical carcinogenesis. In addition, when animals were exposed to ultraviolet light (UV) irradiation, we observed that accumulation of p21WAF1 and cell-cycle arrest were significantly alleviated in the skin of Tg mice as compared to wild-type controls. Most importantly, chronic UV irradiation of Tg mice induced the development of actinic keratosis-like lesions, which are considered in humans as precursors of squamous cell carcinomas (SCC), and subsequently of SCC in a significant proportion of the animals. In contrast, wild-type animals subjected to identical treatments did not develop any type of skin lesions. Thus, the oncoproteins E6 and E7 from beta HPV38 significantly contribute to SCC development in the skin rendering keratinocytes more susceptible to UV-induced carcinogenesis.

No Association between Telomere Length in Peripheral Blood Leukocytes and the Risk of Nonmelanoma Skin Cancer

Recent reports have shown that telomere length was associated with the risk of various cancers, but the results have been inconsistent. We prospectively evaluated the association of telomere length in peripheral blood leukocytes with the risk of skin squamous cell carcinoma (SCC) in 241 cases and 241 controls within the Health Professionals Follow-up Study (HPFS), and the risk of skin basal cell carcinoma (BCC) in 623 cases and 1,943 controls within the Nurses' Health Study (NHS). No significant association was observed between telomere length and risk of SCC (longest quartile vs. shortest quartile, OR = 1.09, 95%CI: 0.62-1.93, P = 0.81). Null findings were also observed between telomere length and risk of BCC in 2 independent sets (OR = 0.96, 95%CI: 0.49-1.87, P = 0.83; and OR = 0.91, 95%CI: 0.66-1.25, P = 0.39). We found no evidence that telomere length in peripheral blood leukocytes was associated with risk of nonmelanoma skin cancer. Our prospective study suggests that telomere length in peripheral blood leukocytes is less likely to play a substantial role in nonmelanoma skin cancer development.

Angiogenesis and host immune response contribute to the aggressive character of non-melanoma skin cancers in renal transplant recipients

The aim of this study was to determine the contribution of tumour angiogenesis to the aggressive growth of non-melanoma skin cancers (NMSCs) in renal transplant recipients (RTRs). The study cohort included RTRs (n = 38) with formalin-fixed paraffin-embedded tumour samples available from first post-transplant NMSC (NMSC1) surgically excised at Christchurch Hospital, New Zealand, from 1997 to 2007. Comparable samples excised from immunocompetent individuals (ICIs) (n = 36) were selected to accommodate confounding factors. Markers of tumour angiogenesis were evaluated by immunohistochemistry, and analysed for associations with clinicopathological variables. As compared with ICIs, RTRs had a higher proportion of tumours with high microvessel density (P = 0.008), high proliferating capillary index (P < 0.0001) and low microvessel pericyte coverage index (P < 0.0001), and RTRs had a shorter cumulative second NMSC (NMSC2)-free interval (P < 0.0001). ICIs had a higher proportion of tumours with a 'marked' number of vascular endothelial growth factor (VEGF)-A-positive leukocytes than RTRs (P = 0.04), and RTRs with a 'moderate/marked' number of VEGF-A-positive leukocytes had longer cumulative NMSC2-free intervals than those with a 'minimum' number (P = 0.02). This study demonstrates increased tumour angiogenesis in NMSC in RTRs, and suggests a role for VEGF-A-positive peritumoural leukocytes in suppressing NMSC development.

Abstract 3673: Expression profile of phosphorylated proteins from the mTOR and Fyn/RSK2 signaling pathways in solar UV-induced skin carcinogenesis

Abstract Chronic sun exposure is considered the main etiologic agent of non-melanoma skin cancer (NMSC). Inactivation of tumor suppressor p53 and activation of key oncogenic signaling pathways important in cell proliferation and transformation are considered crucial steps in the development of NMSC. Therefore, our overall hypothesis is that topically administered small molecule drugs can modulate specific targets in ultraviolet (UV)-induced signaling cascades resulting in attenuation or reversal of carcinogenic events in human skin. In the study herein, we evaluate the modulation of solar light-activated mTOR and Fyn/RSK2 signaling pathways in normal human skin and solar simulated light (SSL)-irradiated human skin to determine the expression profiles of upstream and downstream phosphorylated proteins p38 (Thr180/Tyr182), p44/42 MAPK (Thr202/Tyr204), histone H3 (Ser10), p90RSK (Thr359/Ser363), Akt (Ser473), mTOR (Ser2448), S6 ribosomal protein (Ser235/236), and 4E-BP1 (Thr37/46). The study population consisted of individuals 18 years or older in general good health with skin types II-III. SSL irradiation at various doses ranging from two to four times the minimal erythema dose (MED) was applied to unexposed skin. Punch biopsies were taken at baseline, 5 minutes, 1 h, 5 h, and 24 h post-irradiation and immediately fixed in 10% formalin. Tissues were evaluated by immunohistochemistry for the expression of phospho-proteins. Proliferating cell nuclear antigen (PCNA) and cleaved caspase 3 (Asp175) were evaluated as markers for keratinocyte proliferation and apoptosis, respectively. Marked SSL-induced changes in human epidermis were seen in the expression of phosphorylated histone H3, S6 ribosomal protein, and 4E-BP1 at 1 h, 5 h, and 24 h post-SSL as compared to control. A linear increase in phosphorylated p44/42 MAPK expression was observed at 1 h, 5 h, and 24 h post-SSL as compared to control. Phosphorylated Akt expression increased post-SSL, and appears dependent on duration and intensity of SSL exposure. Ultimately, the expression profile patterns of phosphorylated proteins in the mTOR and Fyn/Rsk2 pathways will be used to determine activity of new and selective chemoprevention agents being developed to target these SSL-induced skin carcinogenesis pathways. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3673. doi:10.1158/1538-7445.AM2011-3673

Abstract 1083: Caveolin-1 in cutaneous squamous cell carcinoma development

Abstract Caveolin-1 (Cav1) is the main protein component of a specialized form of lipid raft termed caveolae and serves to compartmentalize and negatively regulate the activity of signaling molecules involved in cell proliferation and survival. Cav1 has been shown to act as a tumor suppressor in several types of cancer, including breast cancer and melanoma, but its role in the pathogenesis of non-melanoma skin cancer remains largely unexplored. Previous work has indicated that Cav1 is expressed in the basal cell layer of both murine and human epidermis; additionally, loss of Cav1 protein has been shown by our lab to render murine skin more susceptible to papilloma development following treatment with a carcinogenic compound. The purpose of the current study was to further examine the role of Cav1 in non-melanoma skin cancer development using various experimental approaches. Given the previous research, our hypothesis is that Cav1 acts as a suppressor of tumor growth and development in the skin. In order to explore this hypothesis, we have used several experimental systems, including human tissue arrays and loss of function and gain of function studies in animal models of cutaneous squamous cell carcinoma. Manipulation of Cav1 expression in (1) a keratinocyte cell line followed by xenotransplantation and (2) an induced model of skin cancer allowed us to assess the effect of this protein on tumor development, growth, and progression. Using these approaches, we were able to show that Cav1 ablation dramatically increases not only in vitro cell growth and invasion, but also in vivo tumorigenesis, tumor growth, and invasion. In conclusion, these studies provide further evidence in support of the hypothesis that Cav1 acts as a tumor suppressor protein in the skin and serve to identify new potential therapeutic targets in the treatment of cutaneous malignancies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1083. doi:10.1158/1538-7445.AM2011-1083

7,3′,4′-Trihydroxyisoflavone, a Metabolite of the Soy Isoflavone Daidzein, Suppresses Ultraviolet B-induced Skin Cancer by Targeting Cot and MKK4

Nonmelanoma skin cancer is one of the most frequently occurring cancers in the United States. Chronic exposure to UVB irradiation is a major cause of this cancer. Daidzein, along with genistein, is a major isoflavone found in soybeans; however, little is known about the chemopreventive effects of daidzein and its metabolites in UVB-induced skin cancer. Here, we found that 7,3',4'-trihydroxyisoflavone (THIF), a major metabolite of daidzein, effectively inhibits UVB-induced cyclooxygenase 2 (COX-2) expression through the inhibition of NF-κB transcription activity in mouse skin epidermal JB6 P+ cells. In contrast, daidzein had no effect on COX-2 expression levels. Data from Western blot and kinase assays showed that 7,3',4'-THIF inhibited Cot and MKK4 activity, thereby suppressing UVB-induced phosphorylation of mitogen-activated protein kinases. Pull-down assays indicated that 7,3',4'-THIF competed with ATP to inhibit Cot or MKK4 activity. Topical application of 7,3',4'-THIF clearly suppressed the incidence and multiplicity of UVB-induced tumors in hairless mouse skin. Hairless mouse skin results also showed that 7,3',4'-THIF inhibits Cot or MKK4 kinase activity directly, resulting in suppressed UVB-induced COX-2 expression. A docking study revealed that 7,3',4'-THIF, but not daidzein, easily docked to the ATP binding site of Cot and MKK4, which is located between the N- and C-lobes of the kinase domain. Collectively, these results provide insight into the biological actions of 7,3',4'-THIF, a potential skin cancer chemopreventive agent.

Lasers in the Treatment of Nonmelanoma Skin Cancer

Nonmelanoma skin cancers (NMSCs) constitute the largest proportion of cancers worldwide, especially in the Western population, making it essential to develop methods to manage these cancers. Ultraviolet (UV) light being the most significant culprit in the development of NMSCs makes the sun-exposed parts of the body, such as face and extremities, the most vulnerable to develop these tumors. Early diagnosis and emphasis on cosmesis are vital while treating them especially, in patients with multiple squamous and basal cell carcinomas. Lasers seem to be a useful therapeutic modality and are being explored to develop them as a tool for treating skin cancers. To review the use of lasers in the treatment of NMSCs. We reviewed articles that involved the use of lasers in the management of NMSCs and prepared a critical analysis of the same. Lasers as a single modality, as the coherent light source in photodynamic therapy (PDT), or as an adjunct to PDT or other treatment modalities are a potential method of NMSC eradication. Superficial NMSCs and most precancerous cutaneous lesions such as Bowen's disease and actinic keratoses respond best, whereas deeper, more-aggressive NMSCs show poor outcomes with laser treatments.

Enhanced StefinA and Sprr2 expression during papilloma formation in HPV8 transgenic mice

The human papillomavirus type 8 (HPV8) is associated with the development of non-melanoma skin cancer. Transgenic mice expressing the complete early gene region of HPV8 (E6/E7/E1/E2/E4=CER) or E6 separately under the control of the keratin14 promoter spontaneously developed papillomas characterized by varying degrees of epidermal dysplasia. Papilloma growth could be synchronized by a single UVA/B irradiation of the skin, which led to the development of papillomas within three weeks. The objective of this study was to identify alterations in cellular gene expression correlated with HPV8 oncogene expression in transgenic mice. We applied global gene expression profiling by microarray analysis and confirmed deregulation of cellular genes by qRT-PCR and immunohistochemical analysis. By comparison of non-lesional HPV8-CER skin with skin of the parental mouse strain FVB/n, two cellular genes, namely StefinA and Sprr2, coding for precursor proteins of the cornified envelope, were predicted to be strongly upregulated in transgenic skin, which could be confirmed in subsequent qRT-PCR experiments. StefinA and Sprr2 mRNA expression was enhanced until day 7 after UV treatment with higher levels in HPV8 positive skin. While the expression of both genes returned to a normal level in the course of epidermis regeneration in wt mice, the expression persisted elevated in hyperplastic transgenic skin. Staining of an UV induced papilloma of FVB/n wt mouse revealed also strong expression of StefinA and Sprr2 indicating that upregulation in later stages of papilloma formation is independent of HPV8. In non-lesional HPV8-CER transgenic skin StefinA and Sprr2 were found to be indirect/direct transcriptional targets of HPV8.

The E2 protein of human papillomavirus type 8 increases the expression of matrix metalloproteinase-9 in human keratinocytes and organotypic skin cultures

Non-melanoma skin cancer (NMSC) is the most frequent human cancer of Caucasian populations. Although the ultraviolet irradiation is a key contributor to the establishment of this keratinocyte malignancy, the infection by some types of human papillomavirus (HPV) has also been implicated in NMSC development. Cancers occur as a result of a complex series of interactions between the cancer cell and its surrounding matrix. The matrix metalloproteinases (MMPs) play a role in degrading the extracellular matrix. MMP9 is an important gelatinase involved in processes such as cell migration, invasion and metastasis. In this report, we demonstrated by EMSA experiments that the MMP9 promoter contains a binding site for the transcriptional regulator E2 of HPV8. Transient reporter gene assays showed that HPV8-E2 activated the MMP9 promoter in a dose-dependent manner in human epidermal keratinocytes. An E2 transactivation-defective mutant (I73L) as well as a DNA-binding deficient mutant (R433K) demonstrated no activation of the MMP9 promoter, suggesting that both an intact transactivation and DNA-binding domain are required for E2 activation of the MMP9-promoter. The functional role of the E2 binding site within the MMP9 promoter was also confirmed by mutating the E2 binding site. In organotypic cultures of human skin, an overexpression of MMP9 was observed in suprabasal layers of the HPV8 E2-expressing epidermis thus confirming the results of the monolayer cultures. These results demonstrate that the early gene E2 of HPV8 is able to increase the expression of MMP9 by direct activation of the MMP9-promoter.

ASIP genetic variants and the number of non-melanoma skin cancers

Patients with primary non-melanoma skin cancers (NMSCs) tend to develop these cancers at multiple independent sites. We examined the genetic factors in the development of multiple NMSCs among Caucasian women with 28 years of follow-up. We initially evaluated 19 SNPs in nine pigmentation genes with the number of NMSCs in 492 cases and 619 controls without a history of NMSC. We found nominal significant associations between two ASIP gene-related SNPs, rs1885120 and rs910873, and an ASIP haplotype (AH) (rs4911414 allele T and rs1015362 allele G) and an increased number of NMSCs, with p-values of 0.008, 0.01, and 0.01, respectively. We further evaluated these two SNPs and AH haplotype in three data sets. In a joint analysis with 1,507 cases and 4,335 controls, AH haplotype was independently associated with the number of NMSCs with odds ratio (OR) (95% confidence interval (CI)) of 1.45(1.25-1.68) (p-value = 6.2E-07). The AH haplotype was associated with an increased risk of developing one NMSC (OR 1.32; 95% CI, 1.07-1.63). The OR increased to 1.45(1.18-1.78) for those with 2-4 NMSCs and 1.84(1.34-2.53) for those with at least five. The findings suggest that ASIP locus is associated with the number of NMSCs.

On the Relation Between Non-melanoma Skin Cancer and All-cause Mortality Rates

The paper by Jensen et al. (1) reported a 9% [95% con-fidence interval (CI) 7–11%] reduction in mortality rate for patients with basal cell carcinoma (BCC), but a 54% (95% CI, 41–68%) increase for patients with cutaneous squamous cell carcinoma. Smoking is a risk factor for SCC, but not BCC [Ref. 3 in (1)]. Alcohol and tobacco consumption rates are much higher in Denmark than in Sweden. Based on death rates for categories of disease related to alcohol and tobacco, it is estimated that alcohol and smoking account for almost the entire difference between Danish and Swedish men and for 75% of the difference between Danish and Swedish women (2). The role of smoking in the risk of a second cancer after development of non-melanoma skin cancer (NMSC) has been reviewed (3).Further evidence that long-term higher serum 25- hydroxyvitamin D levels are associated with incidence of BCC is provided by a study of cancer cases listed in the Rhineland-Palatinate cancer registry in Germany (4). Those living in the winegrowing regions had a hig-her incidence of NMSC and malignant melanoma but significantly lower risk of vitamin D-sensitive cancers, including those of the stomach, colon, rectum, lung and ovary (5). A similar result was found in Spain, where mortality rates for 15 types of cancer were found to be inversely correlated with NMSC mortality rates (6). While more research is required to more fully under-stand the findings, they add to the evidence supporting the hypothesis that solar ultraviolet irradiance is more beneficial than harmful. In addition to cancer (5), vitamin D reduces the risk of cardiovascular disease and diabetes (7), as well as infectious diseases (8). It has been estimated that a doubling of solar ultraviolet-B irradiance and serum 25-hydroxyvitamin D concentrations in Denmark would reduce the all-cause mortality by 17% (9).

Differential Roles of T‐cell Subsets in Regulation of Ultraviolet Radiation Induced Cutaneous Photocarcinogenesis

Ultraviolet (UV) radiation, in particular the midwavelength range (UVB; 290-320 nm), is one of the most significant risk factors for the development of nonmelanoma skin cancer. UVB radiation-induced immunosuppression, which occurs in both humans and laboratory animals, contributes to their pathogenesis. However, there are conflicting reports on the relative role of CD4(+) and CD8(+) T cells in UVB induced skin cancer. The purpose of this study was to delineate the contribution of these two cell subpopulations to UVB induced immunosuppression and tumor development using C3H/HeN (WT), CD4 knockout (CD4(-/-) ) and CD8 knockout (CD8(-/-) ) mice. We observed that UVB induced skin carcinogenesis was retarded in terms of number of tumors per group, tumor volume and percentage of mice with tumors, in mice deficient in CD4(+) T cells compared with wild-type mice, whereas significantly greater (P < 0.05) numbers of tumors occurred in CD8(-/-) mice. These results indicate that, CD4(+) T cells promote tumor development while CD8(+) T cells have the opposite effect. Further, we found that CD4(+) T cells from tumor-bearing mice produced interleukin (IL)-4, IL-10, and IL-17 whereas CD8(+) T cells produced interferon-γ. Manipulation of T-cell subpopulations that are induced by UVB radiation could be a means of preventing skin cancers caused by this agent.

Chemoprevention of Nonmelanoma Skin Cancer With Celecoxib: A Randomized, Double-Blind, Placebo-Controlled Trial

BackgroundPreclinical studies indicate that the enzyme cyclooxygenase 2 plays an important role in ultraviolet-induced skin cancers. We evaluated the efficacy and safety of celecoxib, a cyclooxygenase 2 inhibitor, as a chemopreventive agent for actinic keratoses, the premalignant precursor of nonmelanoma skin cancers, and for nonmelanoma skin cancers, including cutaneous squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs).MethodsA double-blind placebo-controlled randomized trial involving 240 subjects aged 37–87 years with 10–40 actinic keratoses was conducted at eight US academic medical centers. Patients were randomly assigned to receive 200 mg of celecoxib or placebo administered orally twice daily for 9 months. Subjects were evaluated at 3, 6, 9 (ie, completion of treatment), and 11 months after randomization. The primary endpoint was the number of new actinic keratoses at the 9-month visit as a percentage of the number at the time of randomization. In an intent-to-treat analysis, the incidence of actinic keratoses was compared between the two groups using t tests. In exploratory analyses, we evaluated the number of nonmelanoma skin cancers combined and SCCs and BCCs separately per patient at 11 months after randomization using Poisson regression, after adjustment for patient characteristics and time on study. The numbers of adverse events in the two treatment arms were compared using χ2 or Fisher exact tests. All statistical tests were two-sided.ResultsThere was no difference in the incidence of actinic keratoses between the two groups at 9 months after randomization. However, at 11 months after randomization, there were fewer nonmelanoma skin cancers in the celecoxib arm than in the placebo arm (mean cumulative tumor number per patient 0.14 vs 0.35; rate ratio [RR] = .43, 95% confidence interval [CI] = 0.24 to 0.75; P = .003). After adjusting for age, sex, Fitzpatrick skin type, history of actinic keratosis at randomization, nonmelanoma skin cancer history, and patient time on study, the number of nonmelanoma skin cancers was lower in the celecoxib arm than in the placebo arm (RR = 0.41, 95% CI = 0.23 to 0.72, P = .002) as were the numbers of BCCs (RR = 0.40, 95% CI = 0.18 to 0.93, P = .032) and SCCs (RR = 0.42, 95% CI = 0.19 to 0.93, P = .032). Serious and cardiovascular adverse events were similar in the two groups.ConclusionsCelecoxib may be effective for prevention of SCCs and BCCs in individuals who have extensive actinic damage and are at high risk for development of nonmelanoma skin cancers.

The potential carcinogenic risk of tanning beds: clinical guidelines and patient safety advice

Introduction:In 2009, the WHO listed ultraviolet (UV) radiation as a group 1 carcinogen. In spite of this, each year, millions of people tan indoor in Western countries. The aim of this review is to summarize evidence of tanning bed carcinogenesis and to present guidelines for use of tanning beds and patient safety advice.Methods:A narrative review of the literature was conducted based on both PubMed and Medline searches and on literature review of the retrieved papers.Results:Use of indoor tanning beds represents a significant and avoidable risk factor for the development of both melanoma and nonmelanoma skin cancers. Frequent tanners are more often adolescent females. Tanning beds have additional potential adverse effects such as burns, solar skin damage, infection, and possibly also addictive behavior.Discussion:The effort in preventing UV light-induced carcinogenesis should currently be aimed at developing new strategies for public health information. Tanning beds are one preventable source of UV radiation. In the majority of people solar UV radiation continues to be the major factor and therefore anti-tanning campaigns must always include sunbathers.

Nutrition and nonmelanoma skin cancers

The incidence of nonmelanoma skin cancer is increasing every year. Basal cell carcinoma and squamous cell carcinoma are the two major types of nonmelanoma skin cancer. Among other factors, understanding the potential role of nutrients in the development, progression, and treatment of nonmelanoma skin cancer is critical. This contribution provides a review of the nutrients that have been more extensively investigated in the literature with regard to nonmelanoma skin cancer, including dietary fats, retinol, carotenoids, vitamin C, vitamin D, vitamin E, selenium, copper, iron, zinc, green tea, and black tea.

Cytoplasmic Accumulation of the RNA-binding Protein HuR Stabilizes the Ornithine Decarboxylase Transcript in a Murine Nonmelanoma Skin Cancer Model

Ornithine decarboxylase (ODC) is the first and usually rate-limiting enzyme in the polyamine biosynthetic pathway. Under normal physiological conditions, polyamine content and ODC enzyme activity are highly regulated. However, the induction of ODC activity is an early step in neoplastic transformation. The studies described here use normal mouse keratinocytes (C5N cells), and spindle carcinoma cells (A5 cells) to explore the regulation of ODC in nonmelanoma skin cancer development. Previous results have shown that induction of ODC activity is both necessary and sufficient for the promotion of skin tumors. We see a marked increase in ODC enzyme activity in A5 cells compared with C5N keratinocytes, which correlates with a 4-fold stabilization of ODC mRNA. These data suggest that ODC is post-transcriptionally regulated in skin tumor development. Thus, we sought to investigate whether the ODC transcript interacts with the RNA-binding protein HuR, which is known to bind to and stabilize its target mRNAs. We show that HuR is able to bind to the ODC 3'-UTR in A5 cells but not in C5N cells. Immunofluorescence results reveal that HuR is present in both the nucleus and cytoplasm of A5 cells, whereas C5N cells exhibit strictly nuclear localization of HuR. Knockdown experiments in A5 cells showed that when HuR is depleted, ODC RNA becomes less stable, and ODC enzyme activity decreases. Together, these data support the hypothesis that HuR plays a causative role in ODC up-regulation during nonmelanoma skin cancer development by binding to and stabilizing the ODC transcript.

The potential carcinogenic risk of tanning beds: clinical guidelines and patient safety advice

The potential carcinogenic risk of tanning beds: clinical guidelines and patient safety advice Mette Mogensen1, Gregor BE Jemec21Department of Dermatology, Gentofte Hospital, Hellerup, Denmark; 2Department of Dermatology, Roskilde Hospital, Health Sciences Faculty, University of Copenhagen, Roskilde, DenmarkIntroduction: In 2009, the WHO listed ultraviolet (UV) radiation as a group 1 carcinogen. In spite of this, each year, millions of people tan indoor in Western countries. The aim of this review is to summarize evidence of tanning bed carcinogenesis and to present guidelines for use of tanning beds and patient safety advice.Methods: A narrative review of the literature was conducted based on both PubMed and Medline searches and on literature review of the retrieved papers.Results: Use of indoor tanning beds represents a significant and avoidable risk factor for the development of both melanoma and nonmelanoma skin cancers. Frequent tanners are more often adolescent females. Tanning beds have additional potential adverse effects such as burns, solar skin damage, infection, and possibly also addictive behavior.Discussion: The effort in preventing UV light-induced carcinogenesis should currently be aimed at developing new strategies for public health information. Tanning beds are one preventable source of UV radiation. In the majority of people solar UV radiation continues to be the major factor and therefore anti-tanning campaigns must always include sunbathers.Keywords: tanning beds, skin cancers, melanoma, nonmelanoma

Effect of Physical Activity on Nonmelanoma Skin Cancer Risk in Kidney, Liver, and Pancreatic Transplant Patients

Physical activity has been associated with a lower risk of cancer, including melanoma, but the effect has not yet been assessed for nonmelanoma skin cancer (NMSC). To determine whether the risk of skin cancer differs according to physical activity level in patients at high risk for NMSC. We conducted a retrospective cohort study in kidney, liver, and pancreatic transplant patients via telephone interview. Physical activity scores were calculated for each patient using a previously validated questionnaire. Sun exposure history and skin type were also recorded. The outcome of interest was a biopsy-proven diagnosis of at least one NMSC. Of 142 subjects, 45 (32%) developed NMSC. There was no significant effect of physical activity on the development of NMSC. Physical activity level may not be a major predictor of skin cancer risk in organ transplant patients. Controlled trials and population-based studies are needed to determine whether exercise can decrease the risk of NMSC in the general population. The authors have indicated no significant interest with commercial supporters.

Kaempferol inhibits UVB-induced COX-2 expression by suppressing Src kinase activity

Ultraviolet (UV) radiation is the primary environmental risk factor in the development of nonmelanoma skin cancer, and UVB in particular promotes tumor growth through various signaling pathways. Kaempferol, a flavonoid with anti-inflammatory and anti-oxidative properties, has been studied as a chemopreventive agent; however, little is known regarding its effects on UVB-induced photo-carcinogenesis. Here, we examined the effect of kaempferol on UVB-induced skin inflammation. We found that kaempferol suppressed UVB-induced cyclooxygenase-2 (COX-2) protein expression in mouse skin epidermal JB6 P+ cells and attenuated the UVB-induced transcriptional activities of cox-2 and activator protein-1 ( AP-1). Kaempferol attenuated the UVB-induced phosphorylation of several mitogen-activated protein kinases (MAPKs), including ERKs, p38, and JNKs, but had no effect on the phosphorylation of the upstream MAPK regulator Src. However, in vitro and ex vivo kinase assays demonstrated that kaempferol suppressed Src kinase activity. Furthermore, in vivo data from mouse skin support the idea that kaempferol suppresses UVB-induced COX-2 expression by blocking Src kinase activity. A pull-down assay revealed that kaempferol competes with ATP for direct binding to Src. Docking data suggest that kaempferol docks easily into the ATP-binding site of Src, which is located between the N and the C lobes of the kinase domain. Taken together, these results suggest that kaempferol is a potent chemopreventive agent against skin cancer through its inhibitory interaction with Src.