New Perspectives on Melanoma_ The Role of PAX3

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Unformatted text preview: ,19]. It is also known that PAX3 is highly expressed in melanoma [23‐25,168]. The continued PAX3 expression in postnatal/adult melanocytes, however, requires confirmation [16,17]. If PAX3 is indeed continuously expressed throughout melanocyte cell maturation the following question then remains: what is the role of this developmental regulator in adult differentiated cells? The logical assumption is that the roles would be similar to those of development. In addition, can it be assumed that the roles of PAX3 in melanoma are similar to those in melanoblasts and melanocytes, and if this is correct, does the mere presence of PAX3 in normal melanocytes predispose them to a ‘plastic’ state that increases their tumourigenic potential and then to a more aggressive phenotype upon malignant transformation? Evidence suggests that at least some aspects of developmental PAX3 regulation are active in adult melanocytes and melanoma cells. When PAX3 is transfected into a nontumourigenic mouse melanocyte cell line, it increases proliferation and migration [163], and inhibition of PAX3 results in melanoma growth suppression and increased apoptosis [28]. These results support PAX3 involvement in the regulation of melanocyte proliferation and migration, and similarly in regulation of melanoma cell proliferation and survival. A key role of PAX3 in development is in maintenance of an undifferentiated state, and it may be that PAX3 continues to perform this role in adult melanocytes, so they remain ‘plastic’ and responsive to environmental cues. Moreover, PAX3 may regulate survival and maintenance of melanoma stem‐like cells, allowing their proliferation and migration. In this case PAX3 might play an active role in melanoma‐genesis and metastasis. 27 Chapter I – Thesis Overview Hypothesis: Given the persistent expression of PAX3 in cells of the melanocytic lineage, from the very precursor melanoblast cells of the developing embryo, to postnatal melanocytes, and finally throughout the progression of melanocytic lesions, we hypothesise tha...
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