Section of Dermatology, Department of Medicine, University of Chicago, Chicago IL, USA.
Pigment Cell Melanoma Res. 2010 Apr;23(2):225-37. doi: 10.1111/j.1755-148X.2010.00667.x. Epub 2010 Jan 22.
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.
黑色素瘤是一种分子病理生物学机制尚不清楚的癌症。我们在黑色素瘤细胞系和原发肿瘤中发现了转录因子 PAX3、SOX10、MITF 和酪氨酸激酶受体 MET 的表达。对原发肿瘤标本中 MET 表达的分析显示，40 个样本中有 27 个（68%）显示 MET 表达增加，这种表达与 PAX3、SOX10 和 MITF 的平行表达高度相关。PAX3 和 MITF 独立结合 MET 启动子中的元件，没有协同激活或抑制的证据。SOX10 不能单独直接激活 MET 基因，但可以与 PAX3 或 MITF 协同激活 MET 表达。在黑色素瘤细胞中，有证据表明 PAX3 介导的 MET 诱导有两种途径：（i）直接激活基因，（ii）通过 MITF 间接调节。SK-MEL23 黑色素瘤细胞具有这两种途径，而 SK-MEL28 黑色素瘤细胞只有第一种途径。总之，我们发现 PAX3、SOX10 和 MITF 通过调节 MET 基因在黑色素瘤细胞中发挥积极作用。因此，MET 通过促进迁移、侵袭、抗凋亡和肿瘤细胞生长来促进黑色素瘤的癌症表型。
