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.
Background Our previous experience monitoring nevi in high risk patients by serial digital epiluminescence microscopy (DELM) photography achieved low biopsy rates, but was limited by melanomas presenting as new lesions or arising from nevi that had not been photographed. Objective To determine whether biopsy rates, efficiency of melanoma detection, and melanoma origin (de novo vs. nevus-derived) differed in a similar patient population monitored by total body (TB) photography. Methods 1076 patients (including 187 from prior cohort) underwent TB photography and were monitored using photographs obtained at the initial visit. Risk factors and median monitoring periods for these patients were comparable to patients previously monitored by DELM photography. Results 275 biopsies were performed in 467 patients on follow-up visits. Of 12 melanomas detected on follow-up, five were invasive; five presented as changing lesions and two as new lesions; nine arose de novo and the remainder was nevus-derived. Conclusions In our experience with both approaches, monitoring patients at risk for melanoma by TB (compared to DELM) photography was associated with lower biopsy rates and lower nevus to melanoma ratios, and facilitated detection of both new and changing lesions. In both cohorts, the majority of melanomas detected on follow-up arose de novo.
Survivin expression in melanoma is inversely correlated with patient survival. Transgenic mice harboring melanocyte-specific overexpression of survivin exhibit increased susceptibility to UV-induced melanoma and metastatic progression. To understand the mechanistic basis for metastatic progression, we investigated the effects of survivin on the motility of human melanocytes and melanoma cells. We found that survivin overexpression enhanced migration on fibronectin and invasion through Matrigel, whereas survivin knockdown under subapoptotic conditions blocked migration and invasion. In melanocytes, survivin overexpression activated the Akt and mitogen-activated protein kinase pathways. Akt phosphorylation was required for survivin-enhanced migration and invasion, whereas Erk phosphorylation was required only for enhanced invasion. In both melanocytes and melanoma cells, survivin overexpression was associated with upregulation of α5 integrin (fibronectin receptor component), the antibody-mediated blockade or RNA interferencemediated knockdown of which blocked survivin-enhanced migration. Knockdown of α5 integrin did not affect Akt activation, but inhibition of Akt phosphorylation prevented α5 integrin upregulation elicited by survivin overexpression. Together, our results showed that survivin enhanced the migration and invasion of melanocytic cells and suggested that survivin may promote melanoma metastasis by supporting Akt-dependent upregulation of α5 integrin. Cancer Res; 70(20); 7927-37. ©2010 AACR.
Given its propensity to metastasize, and lack of effective therapies for most patients with advanced disease, early detection of melanoma is a clinical imperative. Although there are no non-invasive techniques for definitive diagnosis of melanoma, and the "gold standard" remains biopsy with histologic examination, a variety of modalities may facilitate early melanoma diagnosis and the detection of new and changing nevi. This article reviews general clinical principles of early melanoma detection, and various modalities that are currently available or on the horizon, providing the clinician with an up-to-date understanding of management strategies for their patients with numerous or atypical nevi.Learning objectives-At the conclusion of this learning activity, participants should: 1) understand the clinical importance of early melanoma detection; 2) appreciate the challenges of early melanoma diagnosis and which patients are at highest risk; 3) know general principles of early melanoma detection; 4) be familiar with current and emerging modalities that may facilitate early melanoma diagnosis and the detection of new and changing nevi; 5) know the advantages and limitations of each modality; and 6) be able to practice a combined approach to the patient with numerous or clinically atypical nevi.
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