PAX3 and SOX10 activate MET receptor expression in melanoma.
Melanoma is a cancer with a poorly understood molecular pathobiology. We find the transcription factors PAX3, SOX10, MITF, and the tyrosine kinase receptor MET expressed in melanoma cell lines and primary tumors. Analysis for MET expression in primary tumor specimens showed 27/40 (68%) of the samples displayed an increased expression of MET, and this expression was highly correlated with parallel expression of PAX3, SOX10, and MITF. PAX3 and MITF bind to elements in the MET promoter independently, without evidence of either synergistic activation or inhibition. SOX10 does not directly activate the MET gene alone, but can synergistically activate MET expression with either PAX3 or MITF. In melanoma cells, there was evidence of two pathways for PAX3 mediated MET induction: (i) direct activation of the gene, and (ii) indirect regulation through MITF. SK-MEL23 melanoma cells have both of these pathways intact, while SK-MEL28 melanoma cells only have the first pathway. In summary, we find that PAX3, SOX10 and MITF play an active role in melanoma cells by regulating the MET gene. In consequence, MET promotes the melanoma cancer phenotype by promoting migration, invasion, resistance to apoptosis, and tumor cell growth.
Mascarenhas
Joseph B
JB
Section of Dermatology, Department of Medicine, University of Chicago, Chicago IL, USA.
Littlejohn
Erica L
EL
Wolsky
Rebecca J
RJ
Young
Kacey P
KP
Nelson
Maria
M
Salgia
Ravi
R
Lang
Deborah
D
D017209:Apoptosis; D045744:Cell Line, Tumor; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000378:metabolism*; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000096:biosynthesis / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis* / Q000378:metabolism; D012313:RNA / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D055757:SOXE Transcription Factors / Q000096:biosynthesis / Q000378:metabolism*
D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; D034741:RNA, Small Interfering; C527923:SOX10 protein, human; D055757:SOXE Transcription Factors; D012313:RNA; D019859:Proto-Oncogene Proteins c-met