Instituto de Biología Molecular de Barcelona, Consejo Superior de Investigaciones Científicas, Parc Científic de Barcelona, Barcelona 08028, Spain.
J Neurosci. 2013 Feb 13;33(7):2773-83. doi: 10.1523/JNEUROSCI.4511-12.2013.
Neuroblastoma is an embryonic tumor derived from cells of the neural crest. Taking advantage of a newly developed neural crest lineage tracer and based on the hypothesis that the molecular mechanisms that mediate neural crest delamination are also likely to be involved in the spread of neuroblastoma, we were able to identify genes that are active both in neural crest development and neuroblastoma tumor formation. A subsequent search of the neuroblastoma gene server for human orthologues of genes differentially expressed in the chick embryo neural crest screen retrieved the LIM domain only protein 4 (LMO4), which was expressed in both cell types analyzed. Functional experiments in these two model systems revealed that LMO4 activity is required for neuroblastoma cell invasion and neural crest delamination. Moreover, we identified LMO4 as an essential cofactor in Snail2-mediated cadherin repression and in the epithelial-to-mesenchymal transition of both neural crest and neuroblastoma cells. Together, our results suggest that the association of high levels of LMO4 with aggressive neuroblastomas is dependent on LMO4 regulation of cadherin expression and hence, tumor invasiveness.
神经母细胞瘤是一种来源于神经嵴细胞的胚胎肿瘤。利用新开发的神经嵴谱系示踪剂，并基于这样的假设，即介导神经嵴分离的分子机制也可能参与神经母细胞瘤的扩散，我们能够鉴定出在神经嵴发育和神经母细胞瘤肿瘤形成中都活跃的基因。随后，在人类神经母细胞瘤基因服务器中搜索鸡胚神经嵴筛选中差异表达的基因的人直系同源物，检索到仅 LIM 结构域蛋白 4（LMO4），它在分析的两种细胞类型中都表达。在这两个模型系统中的功能实验表明，LMO4 活性对于神经母细胞瘤细胞侵袭和神经嵴分离是必需的。此外，我们鉴定出 LMO4 是 Snail2 介导的钙粘蛋白抑制以及神经嵴和神经母细胞瘤细胞的上皮-间充质转化中的必需辅助因子。总之，我们的结果表明，高水平的 LMO4 与侵袭性神经母细胞瘤的关联取决于 LMO4 对钙粘蛋白表达的调节，因此也取决于肿瘤的侵袭性。
