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New Perspectives on Melanoma_ The Role of PAX3

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Unformatted text preview: ells that later give rise to melanocyte precursors, melanoblasts [1,10,11,17,54,63]. Here the main function of Pax3 besides neural crest specification is regulation of melanoblast survival and proliferation [11,12]. Together with SRY (sex determining region Y)‐box 10 (Sox10), Pax3 regulates expression of key melanocyte specification factor Microphthalmia­associated transcription factor (Mitf). It has been suggested that Pax3 controls a “nodal point” in melanocyte differentiation; it simultaneously activates Mitf and represses Dopachrome­ 54 Chapter III – Medic and Ziman, 2010 tautomerase (Dct) transcription thus blocking terminal differentiation [19]. Once Mitf levels reach a certain threshold this repression is removed, allowing Mitf, in the presence of β‐catenin, to activate Dct expression and melanocyte maturation. This model of regulation of melanocyte differentiation suggests that Pax3 expression is either negligible or significantly reduced in adult differentiated melanocytes. Several studies report PAX3 expression in naevi and melanomas [21,23], and show no expression in melanocytes of normal skin [24,25], thus concluding that PAX3 re‐ expression might be involved in melanocyte transformation. In contrast to this widely accepted assumption, other studies note PAX3 expression in melanocytes of normal skin [17,18], and more specifically its upregulation as a result of the UV‐ induced loss of TGFβ signalling from keratinocytes [20]. Additionally, PAX3 expression has been described in cultured melanocytes [16,73] and melanoblasts with no significant change in levels of either mRNA or protein between these two cell types [16]. Here we confirm that PAX3 is present in the majority of naevus and melanoma cells. We also show conclusively that PAX3 is expressed in melanocytes of normal skin where it is co‐expressed with known melanocyte markers. Since the precise role played by PAX3 in melanomas is not clear, we have looked into potential PAX3 regulated pathways within normal melanocytes. We have chosen pathway‐ representative markers that are also downstream targets of PAX3 and...
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