1. ¹Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
2. ²Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
3. ³Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
4. ⁴Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
5. ⁵Department of Biostatistics and Applied Mathematics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

Correspondence: Dr Menashe Bar-Eli, Department of Cancer Biology, Unit 173, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77030, USA. E-mail: mbareli@mdanderson.org

Received 14 April 2006; Revised 12 July 2006; Accepted 24 July 2006; Published online 31 August 2006.

Abstract

The identification of molecular markers of melanoma progression is needed to more accurately stage and identify treatments for patients with malignant melanoma. Previously, we demonstrated that loss of the activator protein-2 (AP-2) expression results in overexpression of the protease-activated receptor-1 (PAR-1) in human melanoma cell lines. Here, we used a tissue microarray platform that consisted of 64 melanocytic lesions, including dysplastic nevi (N=21), primary melanoma (N=20), and metastatic melanoma (N=23). We analyzed the expression of AP-2 and PAR-1 simultaneously by immunofluorescent microscopy with an automated quantification laser scanning cytometer. AP-2 was highly expressed in normal cutaneous melanocytes and dysplastic nevi but not in melanoma metastases. We observed a significantly higher number of AP-2-positive cells in the dysplastic nevi (P=0.0013) and primary melanoma (P=0.0023) compared to the metastatic melanoma. In contrast, we observed a significantly higher percentage of PAR-1-positive cells in the metastatic melanoma compared to dysplastic nevi (P=0.0072) and primary melanoma (P=0.0138). Increased expression of PAR-1 in metastatic melanomas contributes to tumor progression by modulating expression of genes, such as IL-8, matrix metalloproteinase-2, vascular endothelial growth factor, platelet-derived growth factor, and integrins. These findings support our hypothesis that loss of AP-2 is a crucial event in the progression of human melanoma and contributes to the acquisition of the metastatic phenotype via upregulation of PAR-1.