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New Perspectives on Melanoma_ The Role of PAX3


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Unformatted text preview: counterpart PAX7, t(1;13)(p36;q14)) N‐terminus to the C‐terminus of the Forkhead (FKHD) transcription factor [53,153‐156]. Several studies have identified PAX3 as an immunogenic protein in melanoma, with several epitopes known to induce the host immune response [157‐159]. Experimental stimulation of the immune response against PAX3‐expressing tumour cells resulted in melanoma growth suppression and increased apoptosis [157,159]. In addition, inhibition of PAX3 expression by siRNA causes apoptosis in both paediatric rhabdomyosarcoma and melanoma cells [25,28,155,156,160‐162]. All of this evidence highlights the importance of PAX3 in tumourigenesis, clearly supporting its role in anti‐apoptosis. It is not clear however if this is the main or only role for PAX3 in melanoma. Given the importance of PAX3 during embryonic development and suggested role in tumour progression, the possibility that PAX3 plays additional roles in tumourigenesis required further exploration. 23 Chapter I – Thesis Overview iii. SUMMARY Many expression studies provide strong support for PAX3 involvement in melanoma‐genesis, from the primary lesion, through circulating melanoma cells, to metastatic melanoma [21‐26,73,151]. The suggestion that melanoma progression might be driven by melanoma cells showing less differentiated stem‐like phenotype [124,144,147], and the crucial roles that PAX3 plays in regulation of melanocyte stem cells during development, implies that it might replicate these roles in melanoma. The analogy between developmental processes and tumour progression, such as delamination from the site of origin, migration through tissues and adhesion at secondary sites, provide further support for this hypothesis. Moreover, PAX3 is shown to be a nodal point in melanocyte differentiation, since it simultaneously functions to initiate the melanogenic cascade while preventing terminal differentiation, thus keeping the cell in a lineage restricted stem cell‐like state [19]. Its...
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