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New Perspectives on Melanoma_ The Role of PAX3

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Unformatted text preview: cell detachment, growth reduction and increased apoptosis in transfected melanoma cell lines [28]. PAX3‐ As‐transfected cells show increased numbers of p53‐positive cells, but no change in TP53 mRNA levels, confirming that PAX3 regulation of p53 is posttranscriptional [28]. 46 Chapter II – Medic and Ziman, 2009 Additionally, inactivation of the tumour suppressor PTEN is often found in PAX3‐ positive human tumours and tumour cell lines, and its overexpression in tumours results in cell cycle arrest and apoptosis via induction of p27Kip [225]. Transcription of BCL­XL, a member of the BCL­2 family of antiapoptotic genes, is also directly regulated by PAX3 in rhabdomyosarcoma [226]. Treatment with PAX3 or BCL­XL antisense oligonucleotides individually or in combination decreases cell viability to a similar extent, suggesting that they lie in the same antiapoptotic pathway [226]. Additionally, the PAX3 target MITF regulates BCL­2 in melanocytes and melanoma [227]. In a manner similar to its regulation of neural crest‐derived cell migration and possibly melanocyte stem cells from the bulge area of the hair follicle, PAX3 may facilitate dissemination of melanoma cells and metastatic progression. The mechanism by which PAX3 may mediate melanoma metastasis is via regulation of c‐Met, the HGF (hepatocyte growth factor) receptor involved in the regulation of migration and cell motility in development. c‐Met transfection of immortalised melanocytes resulted in their malignant transformation [203]. On the other hand, overstimulation of HGF induces activation of the MAPK pathway and Mitf phosphorylation which in turn induces recruitment of the transcriptional co‐ activator p300. This results in an increase in c­Met mRNA and protein since c‐Met is a direct transcriptional target of Mitf [228]. Thus PAX3 regulates c‐Met either directly or indirectly via Mitf [121,228]. Opposing role(s) of PAX3 and MITF in melanoma Recent microarray analysis of melanoma tissue was able to distinguish two melanoma subgroups; one that is proliferativ...
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