Identification and Characterization of Wnt Signaling Pathway in Keloid Pathogenesis

Igota, Shinichi; Tosa, Mamiko; Murakami, Masahiro; Egawa, Seiko; Shimizu, Hajime; Hyakusoku, Hiko; Ghazizadeh, Mohammad

doi:10.7150/ijms.5349

Cited by 55 publications

(52 citation statements)

References 49 publications

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“…Transforming growth factor-beta (TGF-beta)/Smad signaling plays a key role in excessive fibrosis and keloid formation [6] Wnt signaling also plays key roles in various cellular functions including proliferation, differentiation, survival, apoptosis and migration, [8] which can exacerbate keloid cell proliferation and inhibit keloid cell apoptosis through its interaction with telomerase [16]. …”

Section: Discussionmentioning

confidence: 99%

Identification of a novel mutation in the mechanoreceptor-encoding gene CXCR1 in patients with keloid

et al. 2018

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Keloids are skin fibroproliferative tumors characterized by locally invasive growth of fibroblasts and excessive collagen deposition. The objective of this study is to investigate the molecular basis of the keloid scar by studying the mutation of related genes. We performed gene screening of mechanoreceptors by quantitative polymerase chain reaction (qPCR), Sanger sequencing to detect the CXCR1gene mutation, and immuno-histochemistry to determine CXCR1 protein expression. Among the genes encoding mechanoreceptors, the expression of CXCR1 mRNA was significantly higher in keloid scar tissues than in the surrounding tissues of normal controls (P < 0.05). Sequencing analysis identified a novel missense mutation, c.574G > A (p.Gly192Glu). Immunohistochemistry showed heightened protein expression of CXCR1 in keloid scars as compared to controls. Our findings indicate that CXCR1 gene mutation and altered protein expression are associated with keloid scar development. Identification of the CXCR1 gene mutation might provide insights into the molecular mechanism underlying keloid scar and underscores the potential importance of mechanoreceptors in keloid scar pathogenesis.Electronic supplementary materialThe online version of this article (10.1007/s00403-018-1847-3) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Identification of a novel mutation in the mechanoreceptor-encoding gene CXCR1 in patients with keloid

et al. 2018

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“…Several studies have also suggested that a secreted frizzled-related protein may also be useful as an anti-EMT therapy that inhibits keloid development and/or aggravation. 33,34 Finally, it has been proposed that 5-fluorouracil, which is a pyrimidine analog that is widely used as a cancer chemotherapy, and interferon may also be useful keloid therapies. 35,36 Thus, therapies that regulate EMT may have potential as a therapeutic or prophylactic keloid treatment.…”

Section: Discussionmentioning

confidence: 99%

Examination of Epithelial Mesenchymal Transition in Keloid Tissues and Possibility of Keloid Therapy Target

Kuwahara

Tosa

Egawa

et al. 2016

Plastic and Reconstructive Surgery - Global Open

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Background:Keloid is a fibroproliferative skin disorder that is characterized by collagen accumulation and blood vessel proliferation in the reticular layer of the dermis. It is caused by prolonged inflammation after cutaneous injury. Several studies suggested recently that epithelial mesenchymal transition (EMT) is involved in the development of fibrosis. This study assessed whether EMT also participates in keloid development and/or aggravation.Methods:Resected keloid (n = 19) and normal skin (n = 13) samples were subjected to immunohistochemical, immunofluorescent, and Western blot analyses of their expression of epidermal (E-cadherin) and mesenchymal (vimentin) proteins.Results:Immunohistochemical analysis showed that the keloid tissues had more vimentin-positive cells in the epidermis than the normal tissues. When normal primary keratinocytes were cultured with proinflammatory cytokines, the cobblestone-shaped cells changed to a spindle shape and many vimentin-positive cells were detected. When immortalized HaCaT keratinocytes were cocultured in split-well plates with normal or keloid-derived fibroblasts, they also underwent EMT, as indicated by their greater vimentin expression on Western blot analysis compared with HaCaT cells that were cultured alone.Conclusions:EMT was observed in keloid specimens. EMT was induced by inflammatory cytokines and fibroblasts. EMT may be involved in keloid generation and/or aggravation and may have potential as a keloid treatment target.

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“…Wnt10a is a canonical Wnt ligand that initiates telomerase transcription [39]. There appeared to be some evidence which suggested that the wnt/β-catenin signaling pathway is triggered by Wnt5a in keloid pathogenesis [40]. Sato et al indicated that transforming growth factor (TGF)-β stimulated the Wnt/β-catenin signaling pathway in hypertrophic scar and keloid tissues via the Smad3 and p38 MAPK pathways [41].…”

Section: Discussionmentioning

confidence: 99%

Wnt/β-Catenin Signaling Exacerbates Keloid Cell Proliferation by Regulating Telomerase

Shang

Yuan

et al. 2016

Cell Physiol Biochem

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Objectives: Our goal was to investigate the relationship between keloid and telomerase as well as clarifying the influence of Wnt/β-catenin signaling on keloid cell proliferation. Methods: Tissues from 18 keloid patients were collected for further study. Keloid progenitor cells (KPC) and skin progenitor cells (SKP) were both included in this study. Lenti-virus transfection was used to divide cells into different groups in which cells were treated with different substances: negative control (NC) group, wnt10a siRNA group, β-catenin siRNA group and TERT siRNA group. KPC cells were injected into 20 male BALB/c nude mice in order to build tumor models. Several experiments including immunohistochemistry, western blot and RT-PCR were conducted in order to detect the corresponding protein expressions and relative mRNA levels. MTT assay and flow cytometry were also conducted for assessing cell proliferation and apoptosis status. Results: β-catenin and telomerase expression levels in keloid tissues were elevated compared to normal tissues (all P < 0.05). KPC cells in keloid exhibited more dynamic telomerase activity than SKP cells (P < 0.05). Luciferase activity assay confirmed that β-catenin could directly interact with telomerase. After wnt10a/β-catenin signaling pathway was inhibited, the proliferation of KPC cells was significantly suppressed and the apoptosis rate was remarkably increased (all P < 0.05). Results from tumor models also validated that wnt10a/β-catenin signaling pathway influenced the activity and length of telomerase. Conclusions: Wnt/β-catenin signaling pathway is able to exacerbate keloid cell proliferation and inhibit the apoptosis of keloid cells through its interaction with telomerase.

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Identification and Characterization of Wnt Signaling Pathway in Keloid Pathogenesis

Cited by 55 publications

References 49 publications

Identification of a novel mutation in the mechanoreceptor-encoding gene CXCR1 in patients with keloid

Identification of a novel mutation in the mechanoreceptor-encoding gene CXCR1 in patients with keloid

Examination of Epithelial Mesenchymal Transition in Keloid Tissues and Possibility of Keloid Therapy Target

Wnt/β-Catenin Signaling Exacerbates Keloid Cell Proliferation by Regulating Telomerase

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