New Perspectives on Melanoma_ The Role of PAX3

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Unformatted text preview: s ABCB5 [144,147]. It is therefore suggested to be an indicator of less differentiated and more aggressive melanomas [312] and is implicated in cell migration and metastasis [317]. Stem‐like cell maintenance therefore seems to be the generic role of PAX3, not just in melanocytic but also in other PAX3‐associated lineages (such are muscle and neurons). What is interesting is that PAX3 binding to a common melanocyte and melanoma target SOX9 is significantly higher in melanoma cells. Besides promoting pigmentation, SOX9 might also regulate proliferation, since its overexpression induces a significant decrease in cell proliferation and G1 cell cycle arrest via p21 upregulation (direct binding of SOX9 to p21 promoter) [283]. Additionally, increased levels of SOX9 in melanoma reduce PRAME (preferentially expressed antigen in melanoma) proteins and restore sensitivity to retinoic acid treatment [283]. Therefore, by repressing SOX9 in melanomas, PAX3 might not only drive a less differentiated phenotype, but might also promote their proliferation and drug resistance. PAX3 regulation of melanoma cell proliferation and survival, however, seems to be driven by mechanisms distinct from those in melanocytes; this is in contrast to cell differentiation and migration mediators, commonly regulated by PAX3 in both melanocytes and melanoma cells. These results provide strong support for our hypothesis that PAX3 contributes to melanoma progression by conferring to cells less differentiated, proliferative, migratory, and antiapoptotic properties, leading these cells to a proliferative motile aggressive phenotype in melanoma. 104 Chapter V – General Discussion Proliferative vs. aggressive motile melanoma cell phenotype and how does PAX3 fit into this High levels of cellular heterogeneity are observed in many melanomas with identification of a subpopulation of cells with invasive properties believed to be responsible for tumour dissemination and metastatic seeding. It is not still cle...
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