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New Perspectives on Melanoma_ The Role of PAX3

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Unformatted text preview: a cells, promote cell survival (via PTEN) and proliferation (via TPD52). For the first time, we identify TPD52 as a novel PAX3 target, and this PAX3‐ mediated activation is restricted to melanoma cells rather than melanocytes. Overexpression of TPD52 associated with cellular proliferation is frequently observed in cancer, and in melanoma it is the fifth most upregulated gene [229,271,272]. Thus we show here that PAX3 regulates melanocyte and melanoma proliferation [20,163], and it does so in melanoma via TPD52. We also identify that the clearest difference in PAX3 function between melanoma and melanocytes is in regulating cell survival. PAX3 binds to antiapoptotic factor BCL2L1 and tumour suppressor gene PTEN in melanoma cells. PTEN overexpression results in cell cycle arrest and apoptosis, and mutations and inactivation of this gene are common in tumours [197,225]. Moreover PAX3 was previously reported to repress PTEN transcription in rhabdomyosarcoma and myoblasts [197]. Indeed, we show here strong PAX3 binding and downregulation of PTEN in melanoma. The strong decrease in expression may be exacerbated by the presence of three heterozygous PTEN mutations in A2058 cells including a 35bp deletion and two missense point‐mutations [273]. The mechanism of melanocytes and melanoma cell migration appears to be similar, since it binds to MCAM, CSPG4 and CXCR4 in both cell types, suggesting that the mere presence of PAX3 predisposes both cells to a highly motile phenotype. However, this is the first time that MCAM and CSPG4, known to promote cell motility [274,275], are shown to be direct targets of PAX3. We also confirm PAX3 binding to CXCR4, associated with metastatic spread of melanoma [276]. CXCR4, and its ligand CXCL12, regulate chemotactic migration and “homing” of tumour cells to a secondary organ/site, and facilitate tumour cell extravasation [277,278]. While PAX3 might regulate melanocyte and melanoma cell migration via the same mechanisms, it does so with increased s...
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