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TGF-β1 Induces Polypyrimidine Tract-Binding Protein to Alter Fibroblasts Proliferation and Fibronectin Deposition in Keloid

Human dermal fibrotic disease keloid has been a clinical challenge because of its tumour-like growth and the lack of effective therapy. Dysregulated alternative splicing events have been demonstrated in tumours and fibrosis. In the current study, for the first time, it was demonstrated that the spli...

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Autores principales: Jiao, Hu, Dong, Ping, Yan, Li, Yang, Zhigang, Lv, Xiaoyan, Li, Qiuchen, Zong, Xianlei, Fan, Jincai, Fu, Xin, Liu, Xia, Xiao, Ran
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126665/
https://www.ncbi.nlm.nih.gov/pubmed/27897224
http://dx.doi.org/10.1038/srep38033
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author Jiao, Hu
Dong, Ping
Yan, Li
Yang, Zhigang
Lv, Xiaoyan
Li, Qiuchen
Zong, Xianlei
Fan, Jincai
Fu, Xin
Liu, Xia
Xiao, Ran
author_facet Jiao, Hu
Dong, Ping
Yan, Li
Yang, Zhigang
Lv, Xiaoyan
Li, Qiuchen
Zong, Xianlei
Fan, Jincai
Fu, Xin
Liu, Xia
Xiao, Ran
author_sort Jiao, Hu
collection PubMed
description Human dermal fibrotic disease keloid has been a clinical challenge because of its tumour-like growth and the lack of effective therapy. Dysregulated alternative splicing events have been demonstrated in tumours and fibrosis. In the current study, for the first time, it was demonstrated that the splicing regulator polypyrimidine tract-binding protein (PTB), which plays a pivotal role in tumour proliferation, invasion and metastasis, is overexpressed in keloid tissues and fibroblasts. Additionally, TGF-β1 upregulated the expressions of PTB and its upstream regulator, C-MYC, in keloid fibroblasts. Furthermore, we suppressed PTB using siRNA in keloid fibroblasts and in a keloid xenograft nude mouse model. PTB knockdown significantly slowed the proliferation of keloid fibroblasts and accelerated the regression of transplanted keloid tissues, which was accompanied by a shift in the alternative splicing of USP5 and RTN4. Moreover, when PTB was suppressed, there was a reduction in excessive deposition of FN1 and COL3A1 in transplanted keloid tissues. However, only FN1 was downregulated in keloid fibroblasts that were cultured in media supplemented with TGF-β1. Our study provides evidence for the role of PTB in keloid pathophysiology and offers a novel therapeutic target for keloids. Most importantly, the role TGF-β1 regulation of PTB may provide new insights into the mechanisms underlying inflammatory cytokine-induced fibrosis.
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spelling pubmed-51266652016-12-09 TGF-β1 Induces Polypyrimidine Tract-Binding Protein to Alter Fibroblasts Proliferation and Fibronectin Deposition in Keloid Jiao, Hu Dong, Ping Yan, Li Yang, Zhigang Lv, Xiaoyan Li, Qiuchen Zong, Xianlei Fan, Jincai Fu, Xin Liu, Xia Xiao, Ran Sci Rep Article Human dermal fibrotic disease keloid has been a clinical challenge because of its tumour-like growth and the lack of effective therapy. Dysregulated alternative splicing events have been demonstrated in tumours and fibrosis. In the current study, for the first time, it was demonstrated that the splicing regulator polypyrimidine tract-binding protein (PTB), which plays a pivotal role in tumour proliferation, invasion and metastasis, is overexpressed in keloid tissues and fibroblasts. Additionally, TGF-β1 upregulated the expressions of PTB and its upstream regulator, C-MYC, in keloid fibroblasts. Furthermore, we suppressed PTB using siRNA in keloid fibroblasts and in a keloid xenograft nude mouse model. PTB knockdown significantly slowed the proliferation of keloid fibroblasts and accelerated the regression of transplanted keloid tissues, which was accompanied by a shift in the alternative splicing of USP5 and RTN4. Moreover, when PTB was suppressed, there was a reduction in excessive deposition of FN1 and COL3A1 in transplanted keloid tissues. However, only FN1 was downregulated in keloid fibroblasts that were cultured in media supplemented with TGF-β1. Our study provides evidence for the role of PTB in keloid pathophysiology and offers a novel therapeutic target for keloids. Most importantly, the role TGF-β1 regulation of PTB may provide new insights into the mechanisms underlying inflammatory cytokine-induced fibrosis. Nature Publishing Group 2016-11-29 /pmc/articles/PMC5126665/ /pubmed/27897224 http://dx.doi.org/10.1038/srep38033 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
Jiao, Hu
Dong, Ping
Yan, Li
Yang, Zhigang
Lv, Xiaoyan
Li, Qiuchen
Zong, Xianlei
Fan, Jincai
Fu, Xin
Liu, Xia
Xiao, Ran
TGF-β1 Induces Polypyrimidine Tract-Binding Protein to Alter Fibroblasts Proliferation and Fibronectin Deposition in Keloid
title TGF-β1 Induces Polypyrimidine Tract-Binding Protein to Alter Fibroblasts Proliferation and Fibronectin Deposition in Keloid
title_full TGF-β1 Induces Polypyrimidine Tract-Binding Protein to Alter Fibroblasts Proliferation and Fibronectin Deposition in Keloid
title_fullStr TGF-β1 Induces Polypyrimidine Tract-Binding Protein to Alter Fibroblasts Proliferation and Fibronectin Deposition in Keloid
title_full_unstemmed TGF-β1 Induces Polypyrimidine Tract-Binding Protein to Alter Fibroblasts Proliferation and Fibronectin Deposition in Keloid
title_short TGF-β1 Induces Polypyrimidine Tract-Binding Protein to Alter Fibroblasts Proliferation and Fibronectin Deposition in Keloid
title_sort tgf-β1 induces polypyrimidine tract-binding protein to alter fibroblasts proliferation and fibronectin deposition in keloid
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126665/
https://www.ncbi.nlm.nih.gov/pubmed/27897224
http://dx.doi.org/10.1038/srep38033
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