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

Abstract

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.

• Authors: Hu Jiao, Ping Dong, Li Yan, Zhigang Yang, Xiaoyan Lv, Qiuchen Li, Xianlei Zong, Jincai Fan, Xin Fu, Xia Liu, Ran Xiao
• Journal: Scientific reports (Sci Rep) Vol. 6 Pg. 38033 (11 29 2016) ISSN: 2045-2322 [Electronic] England
• PMID: 27897224 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• FN1 protein, human
• Fibronectins
• TGFB1 protein, human
• Transforming Growth Factor beta1
• Polypyrimidine Tract-Binding Protein

Topics

• Animals
• Cell Proliferation
• Cytokines (biosynthesis)
• Female
• Fibroblasts (metabolism, pathology, transplantation)
• Fibronectins (biosynthesis)
• Heterografts
• Humans
• Keloid (metabolism, pathology)
• Male
• Mice
• Mice, Nude
• Polypyrimidine Tract-Binding Protein (metabolism)
• Transforming Growth Factor beta1 (metabolism)