The Developmental Transcription Factor Neurogenic Differentiation 1 in Migration and Survival of Neuroendocrine Carcinomas



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Differentiation and determination of cell fate during embryogenesis is decided by a collection of transcription factors, including the large family of basic-helix-loop-helix (bHLH) transcription factors. Neurogenic differentiation 1 (NeuroD1) is a bHLH transcription factor responsible for neuronal and neuroendocrine islet differentiation during development of the central and peripheral nervous systems and the pancreas respectively. NeuroD1 has also been shown to be anomalously expressed in a subset of aggressive neuroendocrine tumors. Initial examination of microarray data revealed that subsets of aggressive small cell lung cancers (SCLC) and certain neuroendocrine non-small cell lung cancers (NSCLC-NE) have high expression of NeuroD1 as compared to human bronchial epithelial cells (HBEC) and other non-small cell lung cancers (NSCLC). In several neuroendocrine carcinomas, including subsets of neuroendocrine lung cancers, melanoma and some undifferentiated prostate cell lines, NeuroD1 directly induces the expression of signaling pathways that support survival and migration. Loss-of-function/gain-of-function studies in cell lines from each of these cancer types reveled that NeuroD1 regulates both survival and the migration potential of neuroendocrine carcinomas that have lost or mutated p53. Subsequently, loss of p53 has been shown to up-regulate NeuroD1 expression in non-transformed HBECs and cancer cells with neuroendocrine features. The actions of NeuroD1 are carried out by downstream targets which include the signaling molecules, the tyrosine kinase, tropomyosin-related kinase B (TrkB), and the adhesion molecule, neural cell adhesion molecule (NCAM), and the ion channels, the nicotinic acetylcholine receptor subunit cluster of α3, α5, and β4 (nAChR), to name a few. Impaired expression of each of these downstream targets mirrors the various phenotypes associated with loss of NeuroD1. These findings ultimately have implications for the potential of NeuroD1 acting as a lineage-dependent oncogene in neuroendocrine carcinomas.

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