The Aldo-Keto Reductase AKR1B10 Is Up-Regulated in Keloid Epidermis, Implicating Retinoic Acid Pathway Dysregulation in the Pathogenesis of Keloid Disease

Jumper, Natalie; Hodgkinson, Tom; Arscott, Guyan; Har‐Shai, Yaron; Paus, Ralf; Bayat, Ardeshir

doi:10.1016/j.jid.2016.03.022

Cited by 24 publications

(23 citation statements)

References 125 publications

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“…Our data also identified a significant upregulation of AKR1B10 (as well as AKR1B1 and AKR1B15 ) in all three sites of the KE. This enzyme has a key role in the metabolism of retinoic acid (RA) and our recent study found the induced overexpression of AKR1B10 in NS keratinocytes resulted in significant downregulation of E-cadherin [23]. Additionally, the treatment of keloid fibroblasts with AKR1B10-overexpressing keratinocyte medium resulted in upregulation of TGF β1, Collagen I and collagen III, supporting a role for pathological epithelial-mesenchymal interactions (EMI) in keloid pathogenesis.…”

Section: Resultsmentioning

confidence: 97%

“…Our recent publication on the upregulation of AKR1B10 in KE, where we hypothesised its ability to catalyse the reduction of carbonyls and xenobiotics may render keloid susceptible to chemotherapeutic resistance and thus explain some of the difficulties associated with management of KD to date [23, 151]. Both ALDH1A1 and the aforementioned upregulation of NOTCH4 in KE are also associated with drug resistance [152, 153].…”

Section: Resultsmentioning

confidence: 99%

“…Primary keratinocytes and fibroblasts were established as previously described [22, 23]. In brief, tissue was cut and incubated in Dispase II (10mg/ml; Roche Diagnostics, UK) at 37°C.…”

Section: Methodsmentioning

confidence: 99%

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Site-specific gene expression profiling as a novel strategy for unravelling keloid disease pathobiology

et al. 2017

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Keloid disease (KD) is a fibroproliferative cutaneous tumour characterised by heterogeneity, excess collagen deposition and aggressive local invasion. Lack of a validated animal model and resistance to a multitude of current therapies has resulted in unsatisfactory clinical outcomes of KD management. In order to address KD from a new perspective, we applied for the first time a site-specific in situ microdissection and gene expression profiling approach, through combined laser capture microdissection and transcriptomic array. The aim here was to analyse the utility of this approach compared with established methods of investigation, including whole tissue biopsy and monolayer cell culture techniques. This study was designed to approach KD from a hypothesis-free and compartment-specific angle, using state-of-the-art microdissection and gene expression profiling technology. We sought to characterise expression differences between specific keloid lesional sites and elucidate potential contributions of significantly dysregulated genes to mechanisms underlying keloid pathobiology, thus informing future explorative research into KD. Here, we highlight the advantages of our in situ microdissection strategy in generating expression data with improved sensitivity and accuracy over traditional methods. This methodological approach supports an active role for the epidermis in the pathogenesis of KD through identification of genes and upstream regulators implicated in epithelial-mesenchymal transition, inflammation and immune modulation. We describe dermal expression patterns crucial to collagen deposition that are associated with TGFβ-mediated signalling, which have not previously been examined in KD. Additionally, this study supports the previously proposed presence of a cancer-like stem cell population in KD and explores the possible contribution of gene dysregulation to the resistance of KD to conventional therapy. Through this innovative in situ microdissection gene profiling approach, we provide better-defined gene signatures of distinct KD regions, thereby addressing KD heterogeneity, facilitating differential diagnosis with other cutaneous fibroses via transcriptional fingerprinting, and highlighting key areas for future KD research.

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Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

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Site-specific gene expression profiling as a novel strategy for unravelling keloid disease pathobiology

et al. 2017

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“…However, the response rate was quite uncertain, varying from 50% to 100%. [18,19] The control of recurrence rate was also fluctuating, ranging from less than 10% to over 50%. [20,21] The most common adverse effects included dermal atrophy, telangiectasia and local pain at the injection site.…”

Section: [17]mentioning

confidence: 99%

The radiation therapy in keloids treatment: a comprehensive review of pathomechanism, damage mechanisms and cellular response

Xu¹,

Yang²,

Yu³

et al. 2017

PAR

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“…Although keloid is a benign dermal tumor, its management remains an excessively challenging clinical problem. Keloids do not regress with time, and surgical excision alone is associated with high rates of recurrence [1,3]. Keloid disease is a recurrent fibroproliferative cutaneous tumor of unknown pathogenesis for which clinical management remains unsatisfactory.…”

Section: Introductionmentioning

confidence: 99%

MiR-181a Targets PHLPP2 to Augment AKT Signaling and Regulate Proliferation and Apoptosis in Human Keloid Fibroblasts

Rang

Wang

Pang

et al. 2016

Cell Physiol Biochem

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Background/Aims: Keloids are fibrous overgrowths induced by cutaneous injury. MicroRNAs (miRNAs) have recently emerged as post-transcriptional gene repressors and participants in a diverse array of pathophysiological processes leading to skin disease. The purpose of the current study was to explore the precise functions of miR-181a in human keloid development and the underlying mechanisms. Methods: A miRNA microarray analysis was performed to compare expression profiles between keloid and normal skin tissues. Quantitative real-time PCR was conducted to estimate miR-181a expression. Cell proliferation was determined using the cell counting kit-8 (CCK-8) and 5-ethynyl-2-deoxyuridine (EdU) assays, and cell cycle and apoptosis were detected with flow cytometry. Direct targets of miR-181a were identified using the luciferase reporter assay. Results: miR-181a was significantly upregulated in human keloid tissues and fibroblasts, compared with their control counterparts. Overexpression of miR-181a enhanced keloid fibroblast DNA synthesis and proliferation and inhibited apoptosis, whereas miR-181a suppression triggered the opposite effects. Moreover, miR-181a suppressed the expression of PH domain leucine-rich repeat protein phosphatase 2 (PHLPP2) through direct interactions with its 3′UTR region and subsequently enhanced AKT activation. Overexpression of PHLPP2 without its 3′UTR attenuated the effects of miR-181a on cell proliferation and apoptosis in keloid fibroblast cells. Furthermore, miR-181a mimics increased normal skin fibroblast proliferation. Conclusions: Our results highlight a novel pathway mediated by miR-181a, which may be effectively used as a therapeutic target for treatment of keloids.

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The Aldo-Keto Reductase AKR1B10 Is Up-Regulated in Keloid Epidermis, Implicating Retinoic Acid Pathway Dysregulation in the Pathogenesis of Keloid Disease

Cited by 24 publications

References 125 publications

Site-specific gene expression profiling as a novel strategy for unravelling keloid disease pathobiology

Site-specific gene expression profiling as a novel strategy for unravelling keloid disease pathobiology

The radiation therapy in keloids treatment: a comprehensive review of pathomechanism, damage mechanisms and cellular response

MiR-181a Targets PHLPP2 to Augment AKT Signaling and Regulate Proliferation and Apoptosis in Human Keloid Fibroblasts

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