27022

FOXD3

AIS1|Genesis|HFH2|VAMAS2;forkhead box D3;FOXD3;forkhead box D3

HNF3/FH transcription factor genesis|forkhead box protein D3

1p31.3

protein-coding

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.

The transcription factor forkhead box D3 (FOXD3) plays an important role in the development of neural crest and gastric cancer cells. However, the function and mechanisms of FOXD3 in the breast tumorigenesis and progression is still limited. Here, we report that FOXD3 is a tumor suppressor of breast cancer tumorigenicity and aggressiveness. We found that FOXD3 is down-regulated in breast cancer tissues. Patients with low FOXD3 expression have a poor outcome. Depletion of FOXD3 expression promotes breast cancer cell proliferation and invasion in vitro, whereas overexpression of FOXD3 inhibits breast cancer cell proliferation and invasion both in vitro and in vivo. In addition, depletion of FOXD3 is linked to epithelial-mesenchymal transition (EMT)-like phenotype. Our results indicate FOXD3 exhibits tumor suppressive activity and may be useful for breast therapy.