Expression of AP-2alpha, c-kit, and cleaved caspase-6 and -3 in naevi and malignant melanomas of the skin. A possible role for caspases in melanoma progression?

J Pathol. 2003 Oct;201(2):278-87. doi: 10.1002/path.1424.


Progression of melanoma is associated with loss of the transcription factor AP-2alpha and tyrosine-kinase receptor c-kit. However, the mechanisms by which these two proteins are down-regulated have not been fully elucidated. Fifty non-selected melanomas comprising ten superficial spreading melanomas (five exhibiting a radial growth phase and five a vertical growth phase), ten primary nodular melanomas, 30 melanoma metastases, and 16 naevi were investigated by direct sequencing analysis of the AP-2alpha and c-kit genes and by immunohistochemistry for the respective proteins. Because it has recently been demonstrated that AP-2alpha is preferentially cleaved by caspase-6 and to a lesser extent by caspase-3, immunohistochemistry for the cleaved (activated) forms of caspase-6 (c-casp-6) and caspase-3 (c-casp-3) was carried out. No mutations were identified in the c-kit gene, but three different point mutations were demonstrated in the activation motif of AP-2alpha in four tumours: one vertical growth phase superficial spreading melanoma, one nodular melanoma, and two metastases. Immunohistochemistry revealed progressive loss of the AP-2alpha and c-kit proteins in primary melanomas and metastases when compared with naevi. The decrease of both markers was more accentuated in the dermal component of all primary tumours, with c-kit more affected than AP-2alpha. All invasive melanomas and metastases expressed c-casp-6. c-casp-3 was expressed by 83% of the metastases and in the dermal component of one nodular melanoma. These findings suggest that the loss of AP-2alpha protein expression during the progression of melanoma could be related to mutation of the gene in only a small number of tumours, whereas the expression and activation of caspases, most prominently caspase-6, may be an important factor for the down-regulation of AP-2alpha protein. Furthermore, this study supports recent data that the activation of caspases does not inevitably result in apoptosis, but may also contribute to tumour progression in melanomas.

MeSH terms

  • Caspase 3
  • Caspase 6
  • Caspases / analysis
  • Caspases / genetics*
  • DNA-Binding Proteins / analysis
  • DNA-Binding Proteins / genetics*
  • Disease Progression
  • Enzyme Activation
  • Gene Expression
  • Humans
  • Immunohistochemistry / methods
  • Lymphatic Metastasis
  • Melanoma / genetics*
  • Melanoma / pathology
  • Melanoma / secondary
  • Neoplasm Staging
  • Nevus / genetics*
  • Nevus / pathology
  • Point Mutation
  • Polymerase Chain Reaction
  • Proto-Oncogene Proteins c-kit / analysis*
  • Sequence Analysis, DNA
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / pathology
  • Skin Neoplasms / secondary
  • Statistics, Nonparametric
  • Transcription Factor AP-2
  • Transcription Factors / analysis
  • Transcription Factors / genetics*


  • DNA-Binding Proteins
  • TFAP2A protein, human
  • Transcription Factor AP-2
  • Transcription Factors
  • Proto-Oncogene Proteins c-kit
  • CASP3 protein, human
  • CASP6 protein, human
  • Caspase 3
  • Caspase 6
  • Caspases