Inserm UMR-S1052, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France; LabEX DEVweCAN, 69008 Lyon, France; University Lyon I, 69008 Lyon, France; Université de Lyon, 69000 Lyon, France; Centre Léon Bérard, 69008 Lyon, France.
Cancer Cell. 2013 Oct 14;24(4):466-80. doi: 10.1016/j.ccr.2013.08.018. Epub 2013 Sep 26.
Aberrant expression of embryonic epithelial-mesenchymal transition-inducing transcription factors (EMT-TFs) in epithelial cells triggers EMT, neoplastic transformation, stemness, and metastatic dissemination. We found that regulation and functions of EMT-TFs are different in malignant melanoma. SNAIL2 and ZEB2 transcription factors are expressed in normal melanocytes and behave as tumor-suppressor proteins by activating an MITF-dependent melanocyte differentiation program. In response to NRAS/BRAF activation, EMT-TF network undergoes a profound reorganization in favor of TWIST1 and ZEB1. This reversible switch cooperates with BRAF in promoting dedifferentiation and neoplastic transformation of melanocytes. We detected EMT-TF reprogramming in late-stage melanoma in association with enhanced phospho-ERK levels. This switch results in E-cadherin loss, enhanced invasion, and constitutes an independent factor of poor prognosis in melanoma patients.
胚胎上皮-间充质转化诱导转录因子（EMT-TFs）在上皮细胞中的异常表达会引发 EMT、肿瘤转化、干细胞特性和转移扩散。我们发现 EMT-TFs 在恶性黑色素瘤中的调控和功能是不同的。SNAIL2 和 ZEB2 转录因子在正常黑素细胞中表达，并通过激活 MITF 依赖性黑素细胞分化程序表现为肿瘤抑制蛋白。在 NRAS/BRAF 激活的情况下，EMT-TF 网络发生深刻的重构，有利于 TWIST1 和 ZEB1 的表达。这种可逆转换与 BRAF 协同作用，促进黑素细胞去分化和肿瘤转化。我们在晚期黑色素瘤中检测到 EMT-TF 的重编程，与增强的磷酸化 ERK 水平有关。这种转换导致 E-钙黏蛋白丢失，增强侵袭，并构成黑色素瘤患者预后不良的独立因素。
