| RRC ID |
12764
|
| 著者 |
Huang P, Kishida S, Cao D, Murakami-Tonami Y, Mu P, Nakaguro M, Koide N, Takeuchi I, Onishi A, Kadomatsu K.
|
| タイトル |
The neuronal differentiation factor NeuroD1 downregulates the neuronal repellent factor Slit2 expression and promotes cell motility and tumor formation of neuroblastoma.
|
| ジャーナル |
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.
|
| 巻・号 |
71(8)
|
| ページ |
2938-48
|
| 公開日 |
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 |
9.727
|
| 引用数 |
36
|
|
WOS 分野
|
ONCOLOGY
|
| リソース情報 |
| 遺伝子材料 |
CSII-CMV-RfA-IRES2-Venus (RDB04388)
CSII-CMV-Venus (RDB05553) |
