Neonatal sunburn and melanoma in mice

Noonan, Frances P.; Recio, Juan A.; Takayama, Hisashi; Duray, Paul H.; Anver, Miriam R.; Rush, Walter L.; Fabo, Edward C. De; Merlino, Glenn

doi:10.1038/35095108

Cited by 351 publications

(330 citation statements)

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“…UVB exposure is the primary risk factor in skin-tumour development 46 . A role of zinc in the mechanism of UVB-induced cell death has already been proposed.…”

Section: Discussionmentioning

confidence: 99%

Effects of non-toxic zinc exposure on human epidermal keratinocytes

et al. 2015

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Zinc is an essential microelement; its importance to skin is shown by severe skin symptoms in hereditary or acquired zinc deficiency, by the improvement of several skin conditions using systemic or topical zinc preparations and by the induced intracellular zinc release upon UVB exposure, which is the main harmful environmental factor to skin. Understanding the molecular background of the role of zinc in skin may help to gain insight into the pathology of skin disorders and to provide evidence for the therapeutic usefulness of zinc supplementation.Herein, we studied the effect of zinc chloride (ZnCl 2 ) exposure on the function of HaCaT keratinocytes, and we found that a non-toxic elevation in the concentration of extracellular zinc (100 µM) facilitated cell proliferation and induced significant alterations in the mRNA expression of NOTCH1, IL8, and cyclooxygenase-2. In addition, we detected increased heme oxygenase-1 (HMOX1) expression and non-toxic generation of superoxide in the first 4 h.Regarding the effect on UVB-induced toxicity, although the level of cyclobutane pyrimidine dimers in keratinocytes pre-treated with zinc for 24 h was reduced 3 h after UVB irradiation, we found significantly enhanced superoxide generation 10 h after UVB exposure in the zinc pre-exposed cells. The overall survival was unaffected; however, there was a decrease in the percentage of early apoptotic cells and an increase in the percentage of late apoptotic plus necrotic cells.Our results suggest that exposure of human keratinocytes to non-toxic concentrations of ZnCl 2 impacts gene expression, cell proliferation and the response to environmental stress in skin. It would be important to further examine the role of zinc in skin and to further clarify if this issue can affect our thinking about the pathogenesis of skin diseases.

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“…UVB exposure is the primary risk factor in skin-tumour development 46 . A role of zinc in the mechanism of UVB-induced cell death has already been proposed.…”

Section: Discussionmentioning

confidence: 99%

Effects of non-toxic zinc exposure on human epidermal keratinocytes

et al. 2015

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“…Each year approximately one million new cases of skin cancer are diagnosed in the United States alone, making it the most common type of cancer in this country. In animal models, UV radiation is a complete carcinogen which can initiate and promote skin carcinogenesis resulting in squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and melanoma (de Gruijl et al, 1993;Setlow et al, 1993;Noonan et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Chronic UVA irradiation of human HaCaT keratinocytes induces malignant transformation associated with acquired apoptotic resistance

Huang

et al. 2006

Oncogene

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Ultraviolet A (UVA, 315-400 nm), constituting about 95% of ultraviolet irradiation in natural sunlight, represents a major environmental challenge to the skin and is clearly associated with human skin cancer. It has proven difficult to show direct actions of UVA as a carcinogen in human cells. Here, we demonstrate that chronic UVA exposures at environmentally relevant doses in vitro can induce malignant transformation of human keratinocytes associated with acquired apoptotic resistance. As evidence of carcinogenic transformation, UVAlong-treated (24 J/cm 2 once/week for 18 weeks) HaCaT (ULTH) cells showed increased secretion of matrix metalloproteinase (MMP-9), overexpression of keratin 13, altered morphology and anchorage-independent growth. Malignant transformation was established by the production of aggressive squamous cell carcinomas after inoculation of ULTH cells into nude mice (NC r -nu). ULTH cells were resistant to apoptosis induced not only by UVA but also by UVB and arsenite, two other human skin carcinogens. ULTH cells also became resistant to apoptosis induced by etoposide, staurosporine and doxorubicin hydrochloride. Elevated phosphorylation of protein kinase B (PKB, also called AKT) and reduced expression of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) were detected in ULTH cells. The resistance of ULTH cells to UVA-induced apoptosis was reversed by either inhibition of phosphatidylinositol 3-kinase (PI-3K) or adenovirus expression of PTEN or dominant negative AKT. These data indicate that UVA has carcinogenic potential in human keratinocytes and that the increased AKT signaling and decreased PTEN expression may contribute to this malignant transformation. Further comparisons between the transformed ULTH and control cells should lead to a better understanding of the mechanism of UVA carcinogenesis and may help identify biomarkers for UVA-induced skin malignancies.

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“…For example, in explant models, it has been shown that elevated c-Met expression or Met RTK activity may correlate with metastasis (Rusciano et al 1995). In genetically engineered models, constitutive and ubiquitous HGF expression establishes an autocrine loop with cMet, leading to stepwise development and progression of cutaneous and metastatic melanomas, which cooperates with UVB and Ink4a/Arf deficiency (Otsuka et al 1998;Noonan et al 2001;Recio et al 2002). Correspondingly, while enforced expression of c-Met in melanocytes provides only weak cancer-initiating activity, this mutation drives the development of metastatic disease, and such tumor lesions show concomitant activation of HGF and establishment of HGF-Met signaling loop (L. Chin, unpubl.).…”

Section: Receptor Tyrosine Kinase (Rtks) Activationmentioning

confidence: 99%

Malignant melanoma: genetics and therapeutics in the genomic era

2006

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Cell for cell, probably no human cancer is as aggressive as melanoma. It is among a handful of cancers whose dimensions are reported in millimeters. Tumor thickness approaching 4 mm presents a high risk of metastasis, and a diagnosis of metastatic melanoma carries with it an abysmal median survival of 6-9 mo. What features of this malignancy account for such aggressive behavior? Is it the migratory history of its cell of origin or the programmed adaptation of its differentiated progeny to environmental stress, particularly ultraviolet radiation? While the answers to these questions are far from complete, major strides have been made in our understanding of the cellular, molecular, and genetic underpinnings of melanoma. More importantly, these discoveries carry profound implications for the development of therapies focused directly at the molecular engines driving melanoma, suggesting that we may have reached the brink of an unprecedented opportunity to translate basic science into clinical advances. In this review, we attempt to summarize our current understanding of the genetics and biology of this disease, drawing from expanding genomic information and lessons from development and genetically engineered mouse models. In addition, we look forward toward how these new insights will impact on therapeutic options for metastatic melanoma in the near future. The diseaseMelanomas most often arise within epidermal melanocytes of the skin, although they can also derive from noncutaneous melanocytes such as those lining the choroidal layer of the eye, GI and GU mucosal surfaces, or the meninges. Melanoma is also among the more common causes of "metastatic cancer of unknown primary," which may reflect either a propensity to arise in unexpected sites along the neural crest migratory route, or rapid growth of poorly differentiated lesions arising from indolent or unrecognized cutaneous primary lesions. Clinical staging for primary cutaneous melanoma employs measurements of thickness (in millimeters), presence of ulceration, penetration through cutaneous layers, mitotic rate, evidence of "in transit" metastasis, tumor spread to draining lymph nodes, and evidence of distant metastasis. Management issues in melanoma can be classified in terms of prevention, diagnosis, local disease management, and treatment of metastatic disease.In view of the epidemiological and emerging experimental evidence linking melanoma incidence to UV exposure and skin phototype, prevention and screening strategies represent key areas for reduction of disease incidence and severity. For most cutaneous melanomas in the so-called radial growth phase (e.g., thin melanomas), surgical removal affords curative treatment. In contrast, a significant fraction of patients diagnosed with intermediate-thickness (2-4 mm) cutaneous melanoma eventually succumb to recurrence at regional or distant sites.Critical biological questions facing the melanoma research community include: (1) What genetic and environmental factors contribute to and/or modulate risk of melanom...

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Neonatal sunburn and melanoma in mice

Cited by 351 publications

References 10 publications

Effects of non-toxic zinc exposure on human epidermal keratinocytes

Effects of non-toxic zinc exposure on human epidermal keratinocytes

Chronic UVA irradiation of human HaCaT keratinocytes induces malignant transformation associated with acquired apoptotic resistance

Malignant melanoma: genetics and therapeutics in the genomic era

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