Abstract
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.
Highlights
Aberrant expression of basic helix loop helix transcription factors such as neurogenic differentiation 1 (NeuroD1) and achaete-scute homolog[1] has been observed in aggressive small cell lung cancer (SCLC), neural and neuroendocrine lung carcinomas.[1,2,3,4] the developmental roles of these basic helix loop helix proteins are well established, their possible causative roles in the pathogenesis of neuroendocrine carcinomas are less understood
The consequences of NeuroD1 expression have not been investigated in malignant melanoma, even though it has been suggested to induce neuroendocrine differentiation in conjunction with oncogenic B-RAFV600E under certain circumstances.[17,18]
We observed that NeuroD1, TrkB, and neural cell adhesion molecule (NCAM) expression was greater in melanoma cell lines that were reported to have higher pigmentation and metastatic potential[19,20] (Figure 1b and Supplementary Figure 1a)
Summary
Aberrant expression of basic helix loop helix transcription factors such as neurogenic differentiation 1 (NeuroD1) and achaete-scute homolog[1] has been observed in aggressive small cell lung cancer (SCLC), neural and neuroendocrine lung carcinomas.[1,2,3,4] the developmental roles of these basic helix loop helix proteins are well established, their possible causative roles in the pathogenesis of neuroendocrine carcinomas are less understood. We report that several pigmented melanoma cell lines express high amounts of NeuroD1 and confirmed previous findings in prostate cell lines.[2] We find that regulation of TrkB is conserved across multiple tissue types Downregulation of both NeuroD1 and TrkB prevented viability and migration of several carcinomas; inhibition of TrkB activity only had an effect in cell lines with the neuroendocrine feature as defined by the presence of the neuroendocrine markers synaptophysin and NCAM. We determined that loss of p53 is permissive for increased expression of NeuroD1, possibly in a lineage-dependent manner
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