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New Perspectives on Melanoma_ The Role of PAX3

Although pax3 is recognised as a key embryonic

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Unformatted text preview: te significantly to melanoma progression. Isoform mediated roles The myriad roles detailed for Pax3 may also be mediated by different isoforms during both development and differentiation. A recent in vitro study detailed transcript‐mediated growth characteristics in differentiated melanocytes [163]: PAX3a, b or e transcripts showed decreased proliferation and migration; by contrast PAX3c, d and h transfected melanocytes showed increased proliferation, 49 Chapter II – Medic and Ziman, 2009 migration and survival; PAX3g had no affect on melanocyte proliferation or apoptosis, but reduced migration; and PAX3c, d, g and h isoforms were shown to be associated with anchorage‐independent growth, conferring the ability of otherwise anchorage‐dependant melanocytes to grow in soft‐agar [163]. It is interesting to note that PAX3c increases the migratory ability of transfected melanocytes [163], and microarray analysis of PAX3c‐transfected cells show upregulation of MCAM (also known as MUC18, and CD146) [121,204]. MCAM is frequently upregulated in melanomas [229] and is associated with invasion and metastasis [237]. Notably, expression of PAX3 isoforms varies in different PAX3‐associated cancers: c and d isoforms are predominant in melanoma and small‐cell lung cancer [158,168], and g and h in neuroblastoma [163]; a, b and e are expressed at low or undetectable levels in all of the above tumours [163]. This suggests that full length isoforms might promote tumourigenesis, whereas shortened isoforms might repress tumour propagation. Indeed, microarray analysis showed downregulation of PAX3a and PAX3b transcripts in aggressive melanomas compared to normal melanocytes [238]. One explanation is that shortened PAX3 isoforms may compete with full‐length isoforms and alter or inhibit their function [168]. Since PAX3a and b isoforms lack a homeodomain theoretically they cannot bind Mitf, but may bind and induce TRP­ 1 [76] having an “immediate” effect on melanocyte differentiation. Thus the PAX3‐ induced migration, proliferation and survival of melanocytes may b...
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