RRC ID 12764
Author Huang P, Kishida S, Cao D, Murakami-Tonami Y, Mu P, Nakaguro M, Koide N, Takeuchi I, Onishi A, Kadomatsu K.
Title The neuronal differentiation factor NeuroD1 downregulates the neuronal repellent factor Slit2 expression and promotes cell motility and tumor formation of neuroblastoma.
Journal Cancer Res.
Abstract The basic helix-loop-helix transcription factor NeuroD1 has been implicated in the neurogenesis and early differentiation of pancreatic endocrine cells. However, its function in relation to cancer has been poorly examined. In this study, we found that NeuroD1 is involved in the tumorigenesis of neuroblastoma. NeuroD1 was strongly expressed in a hyperplastic region comprising neuroblasts in the celiac sympathetic ganglion of 2-week-old MYCN transgenic (Tg) mice and was consistently expressed in the subsequently generated neuroblastoma tissue. NeuroD1 knockdown by short hairpin RNA (shRNA) resulted in motility inhibition of the human neuroblastoma cell lines, and this effect was reversed by shRNA-resistant NeuroD1. The motility inhibition by NeuroD1 knockdown was associated with induction of Slit2 expression, and knockdown of Slit2 could restore cell motility. Consistent with this finding, shRNA-resistant NeuroD1 suppressed Slit2 expression. NeuroD1 directly bound to the first and second E-box of the Slit2 promoter region. Moreover, we found that the growth of tumor spheres, established from neuroblastoma cell lines in MYCN Tg mice, was suppressed by NeuroD1 suppression. The functions identified for NeuroD1 in cell motility and tumor sphere growth may suggest a link between NeuroD1 and the tumorigenesis of neuroblastoma. Indeed, tumor formation of tumor sphere-derived cells was significantly suppressed by NeuroD1 knockdown. These data are relevant to the clinical features of human neuroblastoma: high NeuroD1 expression was closely associated with poor prognosis. Our findings establish the critical role of the neuronal differentiation factor NeuroD1 in neuroblastoma as well as its functional relationship with the neuronal repellent factor Slit2.
Volume 71(8)
Pages 2938-48
Published 2011-4-15
DOI 10.1158/0008-5472.CAN-10-3524
PII 0008-5472.CAN-10-3524
PMID 21349947
MeSH Animals Basic Helix-Loop-Helix Transcription Factors / biosynthesis Basic Helix-Loop-Helix Transcription Factors / genetics Basic Helix-Loop-Helix Transcription Factors / metabolism* Cell Growth Processes / physiology Cell Movement / physiology Down-Regulation Ganglia, Sympathetic / metabolism Ganglia, Sympathetic / pathology Gene Amplification Gene Knockdown Techniques Humans Intercellular Signaling Peptides and Proteins / biosynthesis* Intercellular Signaling Peptides and Proteins / genetics Mice Mice, Transgenic Nerve Tissue Proteins / biosynthesis* Nerve Tissue Proteins / genetics Neuroblastoma / genetics Neuroblastoma / metabolism Neuroblastoma / pathology Oncogene Proteins / genetics RNA, Messenger / biosynthesis RNA, Messenger / genetics Spheroids, Cellular
IF 8.378
Times Cited 22
WOS Category ONCOLOGY
Resource
DNA material CSII-CMV-RfA-IRES2-Venus (RDB04388) CSII-CMV-Venus (RDB05553)