SummaryTranscription factors initiate programs of gene expression and are catalysts in downstream molecular cascades that modulate a variety of cellular processes. Pax3 is a transcription factor that is important in the melanocyte and influences melanocytic proliferation, resistance to apoptosis, migration, lineage specificity and differentiation. In this review, we focus on Pax3 and the molecular pathways that Pax3 is a part of during melanogenesis and in the melanocyte stem cell. These roles of Pax3 are emphasized during the development of diseases and syndromes resulting from either too much or too little Pax3 function. Due to its key task in melanocyte stem cells and tumors, the Pax3 pathway may provide an ideal target for either stem cell or cancer therapies.
Melanoma is responsible for an estimated 62 000 new American cancer diagnoses and is projected to cause nearly 8000 deaths in 2008 alone. Although the histogenesis of the tumor is not well understood, it is thought to originate from a rare melanocyte stem cell that resides in the skin. The transcription factor PAX3 has a wellestablished role in the development of melanocytes during embryogenesis, and has recently been characterized as a molecular switch in the mature melanocyte. Based on this function, PAX3 promotes a melanocytic phenotype but blocks terminal differentiation. This mechanism may also contribute to the uncontrolled cell growth and loss of terminal differentiation in melanomas. Here, we find PAX3 expression in 8/8 melanoma cell lines. We also find that PAX3 is commonly expressed in primary melanoma samples (21/58) but significantly less frequently in benign pigmented lesions (9/75). Further analysis of our melanoma set revealed that PAX3 expression is strongly correlated with younger patients with low or no evidence of sun damage. Our data suggest that PAX3-expressing melanomas may be less environmentally dependent and more genetically linked.
Summary
Malignant melanoma tumour cells often carry mutations in the BRAF protein, which activates a second protein called MEK to fuel tumour growth. Using drugs that block the mutant form of BRAF and MEK, we can specifically target and kill most of these tumour cells, but a subset of tumour cells often become resistant to BRAF and MEK inhibiting drugs, and cause the tumour to regrow. The aim of this study was to determine how changes in a protein called CD271, which has previously been shown to increase tumour growth and aggressiveness, contributes to the resistance of BRAF mutant melanoma cells to the MEK inhibiting drug, trametinib. Furthermore, we have previously shown that a cell survival process within tumour cells called autophagy is increased in BRAF mutant melanoma cells, so we also aimed to determine the contribution of autophagy to the resistance of BRAF mutant melanoma cells to trametinib. We show that CD271 and autophagy are increased in advanced malignant melanoma tumours compared to normal moles, and that treatment of melanoma cells in the laboratory with trametinib results in the emergence of a subset of melanoma cells with increased CD271 and autophagy. However, specific inhibition of CD271 reduced the number of resistant melanoma cells following trametinib treatment, while either blocking or activating autophagy resulted in death of trametinib‐resistant melanoma cells. We also show that combined treatment with drugs that specifically block both MEK and autophagy reduced the invasion of trametinib‐resistant melanoma cells in embryonic zebrafish up to 5 days old. Our results show that embryonic zebrafish at an early stage of development may replace mice as a more ethical alternative animal model for the study of cancer metastasis (spreading) and drug response, and highlight an important new way to prevent drug‐resistance by blocking autophagy in patients with BRAF mutant melanoma cells.
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