New Perspectives on Melanoma_ The Role of PAX3

Clinchem 51981988

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Unformatted text preview: within the primary lesion are motile and these cells enter the vasculature; however this same low pigmented phenotype is not maintained at the secondary site, suggesting phenotype switching. They have identified these low pigmented motile melanoma cells as having high BRN2 (PUO class 3 homeobox 2 (POU3F2)) and high TGFβ expression. The phenotype switch is bidirectional, but the preference is from Brn2 high to low, or from low pigmented (less differentiated) motile to more differentiated, pigment‐producing cells. Transcriptional regulator BRN2 (also known as POU3F2, or N‐Oct‐3 and N‐Oct‐5 when it forms a complex with DNA) is also involved in melanocyte differentiation and melanogenesis; high expression is observed in unpigmented melanoma and melanoblast cultures, whereas pigmented melanocytes and melanoma cell lines show low BRN2 expression [16,188,325,326]. BRN2 plays a role in maintaining an undifferentiated melanocytic phenotype through TYR and MITF repression [16,188,325,327], and reduced levels of BRN2 upon differentiation are accompanied by melanosome maturation and increased pigmentation [16,326,328]. Additionally, Brn2 is associated with melanoma cell proliferation, and its regulation has been linked to two major pathways associated with melanoma tumourigenesis. Activation of Brn2, as a result of either oncogenic BRAF activity [329], or Wnt/β‐catenin signaling [330], enhances melanoma cell proliferation. Similarly, BRN2 ablation in melanoma results in decreased proliferation and tumourigenicity [327,331]. Melanoma cells therefore exhibit phenotypic plasticity and toggle between more or less differentiated cells, through a bidirectional reversible process of phenotype switching in response to the environment. This fits into our concept of a role for PAX proteins in adult tissues that is to regulate cell plasticity, driving their response to environmental cues [52]. Factors characterising both proliferative more differentiated (Wnt signalling, and MITF) and less differentiated motile...
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