New Perspectives on Melanoma_ The Role of PAX3

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Unformatted text preview: (BRN2, and TGFβ signalling) phenotype are strongly associated with PAX3. In fact BRN2 has been shown to form protein‐protein interaction with key melanocytic 106 Chapter V – General Discussion transcription factors PAX3 and SOX10 [332], but also to directly bind to the Pax3 promoter to stimulate its expression [221,222]. Even though functional interactions between PAX3 and BRN2 on one side, and TGFβ on the other, further support a link between PAX3 and the ability of melanoma cells to switch phenotype in response to environmental changes, further studies are required to clarify the precise nature of the interaction between these factors. PAX3 could therefore be an intrinsic factor in melanocyte and melanoma cell plasticity, controlling their ‘appropriate’ response. As our results suggest it can promote a less differentiated stem‐like cell phenotype (via HES1, SOX9, NES, DCT), but might also switch cells to an MITF‐driven pigmented, differentiated phenotype; in corroboration we do see PAX3 binding to the MITF promoter in melanoma cells, but not in melanocytes. In melanoma cells PAX3 bound more frequently to genes involved in determining a less differentiated, motile phenotype, compared to those involved in proliferation and survival [3]. This might reflect the characteristics of the metastatic melanoma cell line used here, A2058, shown to have low pigmentation, with high BRN2 levels [16,188,326]. Nevertheless, significantly higher enrichment of TPD52, and PTEN, relative to melanocytes, signifies additional differential regulatory mechanisms are operating in melanoma to regulate their proliferation and survival. By controlling the crucial cellular processes (such as proliferation, cell survival and migration), as well as promoting a less differentiated stem‐like cell phenotypes, PAX3 indeed ‘ticks all the boxes’ as an intrinsic factor driving melanoma development and progression. Moreover, PAX3 seems capable of translating environmental signals into cellular response. 107 Chapter VI – C...
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This document was uploaded on 03/06/2014 for the course CHEMISTRY 12 at National University of Singapore.

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