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Smad4 suppresses the tumorigenesis and aggressiveness of neuroblastoma through repressing the expression of heparanase

Heparanase (HPSE) is the only endo-β-D-glucuronidase that is correlated with the progression of neuroblastoma (NB), the most common extracranial malignancy in childhood. However, the mechanisms underlying HPSE expression in NB still remain largely unknown. Herein, through analyzing cis-regulatory el...

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Autores principales: Qu, Hongxia, Zheng, Liduan, Jiao, Wanju, Mei, Hong, Li, Dan, Song, Huajie, Fang, Erhu, Wang, Xiaojing, Li, Shiwang, Huang, Kai, Tong, Qiangsong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5011643/
https://www.ncbi.nlm.nih.gov/pubmed/27595937
http://dx.doi.org/10.1038/srep32628
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author Qu, Hongxia
Zheng, Liduan
Jiao, Wanju
Mei, Hong
Li, Dan
Song, Huajie
Fang, Erhu
Wang, Xiaojing
Li, Shiwang
Huang, Kai
Tong, Qiangsong
author_facet Qu, Hongxia
Zheng, Liduan
Jiao, Wanju
Mei, Hong
Li, Dan
Song, Huajie
Fang, Erhu
Wang, Xiaojing
Li, Shiwang
Huang, Kai
Tong, Qiangsong
author_sort Qu, Hongxia
collection PubMed
description Heparanase (HPSE) is the only endo-β-D-glucuronidase that is correlated with the progression of neuroblastoma (NB), the most common extracranial malignancy in childhood. However, the mechanisms underlying HPSE expression in NB still remain largely unknown. Herein, through analyzing cis-regulatory elements and mining public microarray datasets, we identified SMAD family member 4 (Smad4) as a crucial transcription regulator of HPSE in NB. We demonstrated that Smad4 repressed the HPSE expression at the transcriptional levels in NB cells. Mechanistically, Smad4 suppressed the HPSE expression through directly binding to its promoter and repressing the lymphoid enhancer binding factor 1 (LEF1)-facilitated transcription of HPSE via physical interaction. Gain- and loss-of-function studies demonstrated that Smad4 inhibited the growth, invasion, metastasis, and angiogenesis of NB cells in vitro and in vivo. Restoration of HPSE expression prevented the NB cells from changes in these biological features induced by Smad4. In clinical NB specimens, Smad4 was under-expressed and inversely correlated with HPSE levels, while LEF1 was highly expressed and positively correlated with HPSE expression. Patients with high Smad4 expression, low LEF1 or HPSE levels had greater survival probability. These results demonstrate that Smad4 suppresses the tumorigenesis and aggressiveness of NB through repressing the HPSE expression.
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spelling pubmed-50116432016-09-12 Smad4 suppresses the tumorigenesis and aggressiveness of neuroblastoma through repressing the expression of heparanase Qu, Hongxia Zheng, Liduan Jiao, Wanju Mei, Hong Li, Dan Song, Huajie Fang, Erhu Wang, Xiaojing Li, Shiwang Huang, Kai Tong, Qiangsong Sci Rep Article Heparanase (HPSE) is the only endo-β-D-glucuronidase that is correlated with the progression of neuroblastoma (NB), the most common extracranial malignancy in childhood. However, the mechanisms underlying HPSE expression in NB still remain largely unknown. Herein, through analyzing cis-regulatory elements and mining public microarray datasets, we identified SMAD family member 4 (Smad4) as a crucial transcription regulator of HPSE in NB. We demonstrated that Smad4 repressed the HPSE expression at the transcriptional levels in NB cells. Mechanistically, Smad4 suppressed the HPSE expression through directly binding to its promoter and repressing the lymphoid enhancer binding factor 1 (LEF1)-facilitated transcription of HPSE via physical interaction. Gain- and loss-of-function studies demonstrated that Smad4 inhibited the growth, invasion, metastasis, and angiogenesis of NB cells in vitro and in vivo. Restoration of HPSE expression prevented the NB cells from changes in these biological features induced by Smad4. In clinical NB specimens, Smad4 was under-expressed and inversely correlated with HPSE levels, while LEF1 was highly expressed and positively correlated with HPSE expression. Patients with high Smad4 expression, low LEF1 or HPSE levels had greater survival probability. These results demonstrate that Smad4 suppresses the tumorigenesis and aggressiveness of NB through repressing the HPSE expression. Nature Publishing Group 2016-09-06 /pmc/articles/PMC5011643/ /pubmed/27595937 http://dx.doi.org/10.1038/srep32628 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Qu, Hongxia
Zheng, Liduan
Jiao, Wanju
Mei, Hong
Li, Dan
Song, Huajie
Fang, Erhu
Wang, Xiaojing
Li, Shiwang
Huang, Kai
Tong, Qiangsong
Smad4 suppresses the tumorigenesis and aggressiveness of neuroblastoma through repressing the expression of heparanase
title Smad4 suppresses the tumorigenesis and aggressiveness of neuroblastoma through repressing the expression of heparanase
title_full Smad4 suppresses the tumorigenesis and aggressiveness of neuroblastoma through repressing the expression of heparanase
title_fullStr Smad4 suppresses the tumorigenesis and aggressiveness of neuroblastoma through repressing the expression of heparanase
title_full_unstemmed Smad4 suppresses the tumorigenesis and aggressiveness of neuroblastoma through repressing the expression of heparanase
title_short Smad4 suppresses the tumorigenesis and aggressiveness of neuroblastoma through repressing the expression of heparanase
title_sort smad4 suppresses the tumorigenesis and aggressiveness of neuroblastoma through repressing the expression of heparanase
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5011643/
https://www.ncbi.nlm.nih.gov/pubmed/27595937
http://dx.doi.org/10.1038/srep32628
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