Keloid fibroblasts are more sensitive to Wnt3a treatment in terms of elevated cellular growth and fibronectin expression

Chua, Alvin Wen Choong; Shen, Gan; Ting, Yixin; Fu, Zhenying; Lim, Che Kang; Song, Colin; Sabapathy, Kanaga; Phan, Toan Thang

doi:10.1016/j.jdermsci.2011.09.008

Cited by 27 publications

(26 citation statements)

References 49 publications

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“…Keloid keratinocytes not only exhibited an increased miR-21-5p level, but also were uniquely able to respond to changes in miR-21-5p levels in our study. Indeed, keloid fibroblasts were also found to be more sensitive to Wnt3a treatment compared with normal fibroblasts34. The different responsiveness to the environmental stimulation could be a real difference between keloid cells and normal skin cells, and the underlying mechanism might give the new light on keloid pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

MiR-21-5p Links Epithelial-Mesenchymal Transition Phenotype with Stem-Like Cell Signatures via AKT Signaling in Keloid Keratinocytes

Cao

Liu

et al. 2016

Sci Rep

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Keloid is the abnormal wound healing puzzled by the aggressive growth and high recurrence rate due to its unrevealed key pathogenic mechanism. MicroRNAs contribute to a series of biological processes including epithelial-mesenchymal transition (EMT) and cells stemness involved in fibrotic disease. Here, using microRNAs microarray analysis we found mir-21-5p was significantly up-regulated in keloid epidermis. To investigate the role of miR-21-5p in keloid pathogenesis, we transfected miR-21-5p mimic or inhibitor in keloid keratinocytes and examined the abilities of cell proliferation, apoptosis, migration and invasion, the expressions of EMT-related markers vimentin and E-cadherin and stem-like cells-associated markers CD44 and ALDH1, and the involvement of PTEN and the signaling of AKT and ERK. Our results demonstrated that up-regulation or knockdown of miR-21-5p significantly increased or decreased the migration, invasion and sphere-forming abilities of keloid keratinocytes, and the phenotype of EMT and cells stemness were enhanced or reduced as well. Furthermore, PTEN and p-AKT were shown to participate in the regulation of miR-21-5p on EMT phenotypes and stemness signatures of keloid keratinocytes, which might account for the invasion and recurrence of keloids. This molecular mechanism of miR-21-5p on keloid keratinocytes linked EMT with cells stemness and implicated novel therapeutic targets for keloids.

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Section: Discussionmentioning

confidence: 99%

MiR-21-5p Links Epithelial-Mesenchymal Transition Phenotype with Stem-Like Cell Signatures via AKT Signaling in Keloid Keratinocytes

Cao

Liu

et al. 2016

Sci Rep

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“…FN1 plays a major role in cell adhesion, migration and differentiation41, and its altered expression has been associated with cancer and fibrosis424344. Fibronectin was found to be strongly expressed in both hypertrophic and keloid tissues compared with normal dermis, and localized to the fibrotic lesions concerned with abnormal scarring mechanisms45.…”

Section: Discussionmentioning

confidence: 99%

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

Jiao

Dong

et al. 2016

Sci Rep

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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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“…In our study, the expression of β-catenin was increased in keloid fibroblasts and tissues compared to the normal fibroblasts. Previous studies showed that β-catenin protein expression is increased in keloid tissues and also Wnt signaling and its effecter β-catenin play an important role in wound healing 29, 39. Wounding of β-catenin overexpressing mice resulted in hyperplastic scar formation 40.…”

Section: Discussionmentioning

confidence: 99%

Identification and Characterization of Wnt Signaling Pathway in Keloid Pathogenesis

Igota¹,

Tosa²,

Murakami³

et al. 2013

Int. J. Med. Sci.

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Keloid is characterized by fibroblastic cell proliferation and abundant collagen synthesis. Numerous studies have shown that the Wingless type (Wnt) signaling pathways play key roles in various cellular functions including proliferation, differentiation, survival, apoptosis and migration. The aim of this study was to clarify the role of Wnt signaling pathway in keloid pathogenesis. Primary fibroblast cultures and tissue samples from keloid and normal appearing dermis were used. The expression of Wnt family members, frizzled (FZD)4 receptor, receptor tyrosine kinase-like orphan receptor (ROR)2 and the Wnt signaling downstream targets, glycogen synthase kinase (GSK)3-β and β-catenin were assessed using semi-quantitative RT-PCR, Western blot, or immunohistochemical methods. Of the Wnt family members, Wnt5a mRNA and protein levels were elevated in keloid fibroblasts (KF) as compared to normal fibroblasts (NF). A higher expression of β-catenin protein was also found in KF. No detectable levels of FZD4 receptor and ROR2 proteins were observed in both NF and KF. Functional analysis showed that treatment of NF and KF with recombinant Wnt5a peptide resulted in an increase in protein levels of total β-catenin and phosphorylated β-catenin at Ser33/37/Thr 41 but no significant change in phosphorylated β-catenin at Ser45/Thr 41 positions. In addition, the expression of total GSK3-β protein was not affected but its phosphorylated/inactivated form was increased in NF and KF. Our findings highlight a potential role for a Wnt/β-catenin canonical signaling pathway triggered by Wnt5a in keloid pathogenesis thereby providing a new molecular target for therapeutic modulations.

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Keloid fibroblasts are more sensitive to Wnt3a treatment in terms of elevated cellular growth and fibronectin expression

Cited by 27 publications

References 49 publications

MiR-21-5p Links Epithelial-Mesenchymal Transition Phenotype with Stem-Like Cell Signatures via AKT Signaling in Keloid Keratinocytes

MiR-21-5p Links Epithelial-Mesenchymal Transition Phenotype with Stem-Like Cell Signatures via AKT Signaling in Keloid Keratinocytes

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

Identification and Characterization of Wnt Signaling Pathway in Keloid Pathogenesis

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