Members of the Bcl-2 family of antiapoptotic proteins (Bcl-2, Bcl-XL and Mcl-1) are key regulators of apoptosis. The purpose of the present study was to examine and better define the role of Bcl-2, Bcl-XL and Mcl-1 in the progression of melanoma. Immunohistochemical staining for Bcl-2, Bcl-XL and Mcl-1 was performed on paraffin sections of 100 cases of benign nevi, primary melanoma and metastatic melanoma. Expression was correlated with histopathologic features, clinical progress and expression of transcription factors (AP-2, MITF and p-Stat3). Bcl-2 was expressed in 100% of benign nevi and thin melanoma (r1.0 mm) but was less in thick melanoma (41.0 mm) (88%), subcutaneous (62%) and lymph node metastases (35%). In contrast, Bcl-XL and Mcl-1 were expressed at lower levels in nevi and thin melanoma compared to Bcl-2 but their expression was much higher in thick melanoma and in subcutaneous and lymph node metastases (Po0.0001). Bcl-2 expression was negatively associated with tumor thickness (Po0.05) but Bcl-XL expression increased with increasing tumor thickness (Po0.05) and dermal tumor mitotic rate (Po0.05). Similarly Mcl-1 expression increased with increasing tumor thickness (Po0.09) and dermal tumor mitotic rate (Po0.17). Bcl-2 expression was positively correlated with expression of the transcription factors microphthalmia transcription factor (MITF) and nuclear AP-2 whereas Bcl-XL (and Mcl-1) expression were positively correlated with p-Stat3. This study is the first to show a clear dissociation between changes in Bcl-2 expression (downregulation) and Bcl-XL, Mcl-1 expression (upregulation) during progression of melanoma. The results were also consistent with a role for AP-2 and MITF in regulation of Bcl-2 and pStat3 in regulation of Bcl-XL. These findings have important implications for the development of treatments targeting antiapoptotic proteins in patients with melanoma. Modern Pathology (2007) 20, 416-426.

No abstract

Epidermal melanin reduces some effects of UV radiation, the major cause of skin cancer. To examine whether induced melanin can provide protection from sunburn injury, 65 subjects completed a trial with the potent synthetic melanotropin, [Nle4-D-Phe7]-alpha-melanocyte-stimulating hormone ([Nle4-D-Phe7]-alpha-MSH) delivered by subcutaneous injection into the abdomen at 0.16 mg/kg for three 10-day cycles over 3 months. Melanin density, measured by reflectance spectroscopy, increased significantly in all [Nle4-D-Phe7]-alpha-MSH-treated subjects. The highest increases were in volunteers with lowest baseline skin melanin levels. In subjects with low minimal erythemal dose (MED) skin type, melanin increased by an average of 41% (from 2.55 to 3.59, P < 0.0001 vs placebo) over eight separate skin sites compared with only 12% (from 4.18 to 4.70, P < 0.0001 vs placebo) in subjects with a high-MED skin type. Epidermal sunburn cells resulting from exposure to 3 MED of UV radiation were reduced by more than 50% after [Nle4-D-Phe7]-alpha-MSH treatment in the volunteers with low baseline MED. Thymine dimer formation was also shown to be reduced by 59% (P = 0.002) in the epidermal basal layer. This study has shown for the first time the potential ability of a synthetic hormone that augments melanin production to provide photoprotection to people who normally burn in direct sunlight.