Differential LEF1 and TCF4 expression is involved in melanoma cell phenotype switching
Differential LEF1 and TCF4 expression is involved in melanoma cell phenotype switching
复制标题
DOI：
10.1111/j.1755-148x.2011.00871.x
复制
发表时间：
2011-08-01
影响因子：
4.3
通讯作者：
Hoek, Keith S.
中科院分区：
文献类型：
--
作者：
Eichhoff, Ossia M.;Weeraratna, Ashani;Hoek, Keith S.
最近的观察表明，黑色素瘤细胞通过在增殖和侵袭表型状态之间来回切换来驱动疾病进展。表型转换与Wnt信号传导的变化有关，因此我们寻找β -连环蛋白及其LEF/TCF辅助因子的水平和活性的细胞表型特异性差异。我们发现，虽然细胞质β -连环蛋白的分布是表型特异性的（在增殖细胞中与膜相关，在浸润细胞中与细胞质相关），但其核分布和活性不是。相反，两种β -连环蛋白辅助因子LEF1和TCF4的表达模式都是表型特异性的，并且呈负相关。LEF1在分化/增殖性表型细胞中优先表达，TCF4在去分化/侵袭性表型细胞中优先表达。敲除实验证实，这些辅助因子对M-MITF、WNT5A等基因的表型特异性表达具有重要作用，并且LEF1独立于β -catenin抑制TCF4的表达。我们的数据表明，黑色素瘤细胞表型转换行为受LEF1/TCF4活性差异的调节。
Recent observations suggest that melanoma cells drive disease progression by switching back and forth between phenotypic states of proliferation and invasion. Phenotype switching has been linked to changes in Wnt signalling, and we therefore looked for cell phenotype-specific differences in the levels and activity of beta-catenin and its LEF/TCF co-factors. We found that while cytosolic beta-catenin distribution is phenotype-specific (membrane-associated in proliferative cells and cytosolic in invasive cells), its nuclear distribution and activity is not. Instead, the expression patterns of two beta-catenin co-factors, LEF1 and TCF4, are both phenotype-specific and inversely correlated. LEF1 is preferentially expressed by differentiated/proliferative phenotype cells and TCF4 by dedifferentiated/invasive phenotype cells. Knock-down experiments confirmed that these co-factors are important for the phenotype-specific expression of M-MITF, WNT5A and other genes and that LEF1 suppresses TCF4 expression independently of beta-catenin. Our data show that melanoma cell phenotype switching behaviour is regulated by differential LEF1/TCF4 activity.