Oncotarget

Research Papers:

FOXD3 is a novel tumor suppressor that affects growth, invasion, metastasis and angiogenesis of neuroblastoma

Dan Li, Hong Mei, Meng Qi, Dehua Yang, Xiang Zhao, Xuan Xiang, Jiarui Pu, Kai Huang, Liduan Zheng and Qiangsong Tong _

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Oncotarget. 2013; 4:2021-2044. https://doi.org/10.18632/oncotarget.1579

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Abstract

Dan Li1,#, Hong Mei1,#, Meng Qi1,#, Dehua Yang1, Xiang Zhao1, Xuan Xiang1, Jiarui Pu1, Kai Huang2,3, Liduan Zheng2,4, Qiangsong Tong1,2

1Department of Pediatric Surgery, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China

2Clinical Center of Human Genomic Research, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China

3Department of Cardiology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China

4Department of Pathology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China

#Denotes equal contribution

Correspondence:

Qiangsong Tong, email:

Correspondence:

Liduan Zheng, email:

Keywords: neuroblastoma, forkhead box D3, N-myc downstream regulated 1

Received: September 9, 2013 Accepted: September 30, 2013 Published: November 5, 2013

Abstract

The transcription factor forkhead box D3 (FOXD3) plays a crucial role in the development of neural crest cells. However, the function and underlying mechanisms of FOXD3 in the progression of neuroblastoma (NB), an embryonal tumor that is derived from the neural crest, still remain largely unknown. Here, we report that FOXD3 is an important oncosuppressor of NB tumorigenicity and aggressiveness. We found that FOXD3 was down-regulated in NB tissues and cell lines. Patients with high FOXD3 expression have greater survival probability. Over-expression or knockdown of FOXD3 responsively altered both the protein and mRNA levels of N-myc downstream regulated 1 (NDRG1) and its downstream genes, vascular endothelial growth factor and matrix metalloproteinase 9, in cultured NB cell lines SH-SY5Y and SK-N-SH. Luciferase reporter and chromatin immunoprecipitation assays indicated that FOXD3 directly targeted the binding site within NDRG1 promoter to facilitate its transcription. Ectopic expression of FOXD3 suppressed the growth, invasion, metastasis and angiogenesis of SH-SY5Y and SK-N-SH cells in vitro and in vivo. Conversely, knockdown of FOXD3 promoted the growth, migration, invasion and angiogenesis of NB cells. In addition, rescue experiments in FOXD3 over-expressed or silenced NB cells showed that restoration of NDRG1 expression prevented the tumor cells from FOXD3-mediated changes in these biological features. Our results indicate that FOXD3 exhibits tumor suppressive activity that affects the growth, aggressiveness and angiogenesis of NB through transcriptional regulation of NDRG1.


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