NeuroD1 regulation of migration accompanies the differential sensitivity of neuroendocrine carcinomas to TrkB inhibition.
NeuroD1 regulation of migration accompanies the differential sensitivity of neuroendocrine carcinomas to TrkB inhibition.
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DOI：
10.1038/oncsis.2013.24
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发表时间：
2013-08-19
期刊：
影响因子：
6.2
通讯作者：
Cobb, M. H.
中科院分区：
文献类型：
--
作者：
Osborne, J. K.;Larsen, J. E.;Gonzales, J. X.;Shames, D. S.;Sato, M.;Wistuba, I. I.;Girard, L.;Minna, J. D.;Cobb, M. H.
发育转录因子NeuroD1在侵袭性神经内分泌肿瘤的一个亚群中异常表达。以前，我们证明了TrkB和神经细胞粘附分子（NCAM）是NeuroD1的下游靶点，有助于神经内分泌肺中神经源性分化1（NeuroD1）的作用。我们发现几种恶性黑色素瘤和前列腺细胞系表达NeuroD1和TrkB。抑制TrkB活性降低了几种神经内分泌色素性黑色素瘤的侵袭，但在前列腺细胞系中没有。我们还发现，在正常人支气管上皮细胞和具有神经内分泌特征的癌细胞中，肿瘤抑制因子p53的缺失增加了NeuroD1的表达。虽然我们发现NeuroD1的主要作用机制是通过调节TrkB，但有效靶向TrkB以抑制侵袭可能取决于细胞来源。这些发现表明NeuroD1是一种谱系依赖性癌基因，通过其下游靶点TrkB在多种癌症类型中发挥作用，这可能为神经内分泌癌的发病机制提供新的见解。
The developmental transcription factor NeuroD1 is anomalously expressed in a subset of aggressive neuroendocrine tumors. Previously, we demonstrated that TrkB and neural cell adhesion molecule (NCAM) are downstream targets of NeuroD1 that contribute to the actions of neurogenic differentiation 1 (NeuroD1) in neuroendocrine lung. We found that several malignant melanoma and prostate cell lines express NeuroD1 and TrkB. Inhibition of TrkB activity decreased invasion in several neuroendocrine pigmented melanoma but not in prostate cell lines. We also found that loss of the tumor suppressor p53 increased NeuroD1 expression in normal human bronchial epithelial cells and cancer cells with neuroendocrine features. Although we found that a major mechanism of action of NeuroD1 is by the regulation of TrkB, effective targeting of TrkB to inhibit invasion may depend on the cell of origin. These findings suggest that NeuroD1 is a lineage-dependent oncogene acting through its downstream target, TrkB, across multiple cancer types, which may provide new insights into the pathogenesis of neuroendocrine cancers.
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