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New Perspectives on Melanoma_ The Role of PAX3

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Unformatted text preview: e and weakly metastatic with a neural crest‐like transcriptional signature maintained through Wnt signalling; the other that is strongly metastatic showing upregulation of genes involved in modifying the extracellular environment through TGFβ signalling [125,229]. Induction of TGFβ‐like signalling in melanoma may inhibit Wnt signalling by activating the 47 Chapter II – Medic and Ziman, 2009 expression of Wnt‐inhibitors, leading to less proliferative but more metastatic melanoma cells. Given that microarray data reflect the profile of the majority of cells within the tumour, it is possible that individual melanoma cells possess different metastatic potential determined by their individual gene expression profile; more differentiated melanoma cells expressing differentiation genes under Wnt signalling would have low metastatic potential whereas less differentiated and more stem cell‐like melanoma cells would have higher metastatic potential regulated by TGFβ. PAX3 is known to directly regulate TGFβ [58], whereas MITF is functionally regulated by Wnt3a [111]. Interestingly, levels of MITF are an important determinant of melanoma cell fate: depletion or complete loss of MITF results in cell cycle arrest and/or apoptosis; increased expression levels favour differentiation; and intermediate levels promote proliferation [193,227]. Indeed, overexpression of Mitf in a highly aggressive melanoma cell line resulted in morphological and behavioural changes towards a more differentiated and less aggressive phenotype, evident by an increase in Tyr and TRP­1 expression, as well as an increase in p21 and p27 and arrest in G2/G1 cell cycle stage, together with a decrease in Ki57 and an increase in Bcl‐2 [230]. Compared to the original cell line, altered melanoma cells were less tumourigenic as evidenced by later development of tumours and lack of liver metastases in injected mice. PAX3 and MITF lie on the opposing sides of the differentiation regulation pathway, determining les...
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