New Perspectives on Melanoma_ The Role of PAX3

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Unformatted text preview: 3 are operational in adult melanocytes and might continue in melanoma. Logically the next focus of our study was to investigate PAX3 involvement in several developmental regulatory processes, namely, differentiation, proliferation, survival and migration, in both melanocytes and melanoma cells. PAX3 in normal skin melanocyte The role of PAX3 in melanocyte differentiation is probably the best described role for PAX3 thus far, balancing melanocyte differentiation with maintenance of the undifferentiated state [13,19]. We decided to better characterise PAX3‐expressing melanocytes in terms if their differentiation status, utilising previously identified markers of a more or less differentiated state, namely MLANA and HES1, respectively. MLANA is a type III membrane protein, indispensable for correct functioning of the structural melanosomal protein PMEL, and for pigmentation [96]. Like other melanogenic genes (TYR, TYRP1, DCT, and PMEL), MLANA expression is transcriptionaly regulated by MITF, a direct PAX3 dowstream target [68‐71]. MLANA therefore marks melanocytes that are further down the 97 Chapter V – General Discussion differentiation path. By contrast, the transcriptional repressor HES1, another direct target of PAX3 [122,123], is found in undifferentiated melanocyte stem cells of the hair follicle [194]. During the hair cycle, melanocytes are known to progress through stages of differentiation and maturation, closely associated with their location in the growing follicle, namely bulge melanocyte stem cells, their differentiating progeny along the outer root sheath (ORS) and finally mature matrix melanocytes [254]. Utilising co‐expression analysis of PAX3 with MLANA or HES1, we identified the differentiation status of follicular and epidermal melanocytes; from less differentiated PAX3, MITF and HES1 positive cells, to more differentiated PAX3, MITF and MLANA positive cells, and also identified PAX3‐negative, MITF and MLANA positive cells, which are presumably fully mature melanocytes. We found that epidermal melanocytes resemble transit amplifying cells of the outer root sheath, sh...
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