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New Perspectives on Melanoma_ The Role of PAX3

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Unformatted text preview: whereas the shorter isoform 2 (also known as Bcl‐s) is proapoptotic [288]. These two transcripts do however share the same promoter, in which case we cannot be sure which of them is regulated by PAX3 in our experiments. Both of the transcripts are shown to be expressed in normal skin and melanoma samples, but in different proportions [255]. Presumably the most likely explanation is that the antiapoptotic role of PAX3 in melanocytes is via other factors and not BCL2L1. An interesting observation is that a proportion of epidermal melanocytes in sun exposed normal skin are proliferative [2]. A causal relationship has been established between sun exposure, PAX3 upregulation and increased melanocyte proliferation [20]. Cyclin A2 (CCNA2) is upregulated in melanocytes following PAX3 transfection [121], and in our ChIP experiments we observed low enrichment of the CCNA2 promoter in melanocytes, suggesting that PAX3 regulation of melanocytic proliferation might be via this general cell cycle regulator. However, PAX3 binding to CCNA2 is much more prominent in the melanoma cell line. PAX3‐ knockdown in melanoma cells has been shown to inhibit cell proliferation; and induce cell cycle arrest in S and G2/M phases, both of which require CCNA for progression through S phase and entry to M phase [27]. These results further support regulation of proliferation, as a generic role for PAX3, in both melanocytes and melanoma cells. 101 Chapter V – General Discussion Besides its expected involvement in melanocyte differentiation and survival, it is interesting to observe PAX3 binding to promoters of genes associated with migration, namely MCAM, CSPG4 and CXCR4, suggesting that regulation of migration is a common feature of PAX3 in melanocytes, as it is during development and tumourigenesis. It also suggests that melanocytes have an intrinsic propensity to migrate. This feature is required for normal hair follicle regeneration [289], and sub‐bulge region of hair follicle shows overexpression of MCAM in outer root sheath, where melanocytes reside [192]. Consistent...
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