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New Perspectives on Melanoma_ The Role of PAX3

The authors further suggest that the presence of a

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Unformatted text preview: ferential mechanisms of PAX3 regulation in melanoma In addition to PAX3‐regulated processes that are common in melanocytes and melanoma cells, such as stem‐like cell maintenance, proliferation and migration, we have identified here some melanoma exclusive PAX3 targets, such as TPD52 and PTEN, which may differentially mediate melanoma cell proliferation, and prevent apoptosis. TPD52 has a role in membrane trafficking and its overexpression has been reported in numerous cancers [304‐308]; in melanoma it is the fifth most highly upregulated gene [229]. PTEN mutations and inactivation are often found in tumours, and overexpression of functional PTEN results in cell cycle arrest and apoptosis [197,225,309]. PAX3 was previously reported to repress PTEN transcription in rhabdomyosarcoma and myoblasts [197], and here we show that it might do the same in melanoma. Normally, PTEN regulates progression through the G1 cell cycle check point, by negatively regulating PI3K/AKT signalling, through the cell cycle inhibitor (CDK inhibitor) p27Kip1 [197]. PTEN also directly regulates p53 activity [198,199]. Loss of functional PTEN (due to mutations or transcriptional suppression) results in the loss of apoptosis and uncontrolled proliferation. Another differential PAX3 target in melanoma cells is intermediate filament Nestin (NES), a neuroectodermal stem and progenitor cell marker that is also present in hair follicle stem cells [310,311]. Its expression has been reported in melanocytes, naevi and melanomas [312‐315]. In melanomas stronger staining and increased 103 Chapter V – General Discussion numbers of NES positive cells correlate with more advanced stages [312]. NES‐ positive stage I and II melanomas correlate with worse prognosis [315], and increased numbers of NES‐positive circulating melanoma cells correlate with tumour burden, number of metastatic sites and to shorter overall survival [316]. NES marks a subpopulation of melanoma cells with stem cell like properties, as doe...
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