Inhibition of microRNA-21-5p reduces keloid fibroblast autophagy and migration by targeting PTEN after electron beam irradiation

Li, Yan; Wang, Lian-Zhao; Xiao, Ran; Cao, Rui; Pan, Bo; Lv, Xiaoyan; Jiao, Hu; Zhuang, Qiang; Sun, Xuefeng; Liu, Yuanbo

doi:10.1038/s41374-019-0323-9

Cited by 27 publications

(30 citation statements)

References 34 publications

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“…The epigenetic modification based on ncRNA also shows great application potential during keloid treatment. An exciting study found that EB irradiation inhibited autophagy in KFs by reducing miR-21-5p, which has already been confirmed to be closely involved in keloid progression, thereby indicating the significance of miR-21-5p-targeting therapy in controlling the keloid recurrence [98]. Furthermore, in a double-blinded, placebo-randomized, within-subject controlled clinical trial of single and multiple ascending doses of remlarsen in normal healthy volunteers, Gallant-Behm et al found that miR-29b mimic (remlarsen) repressed ECM expression and the development of fibroplasia.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 92%

Epigenetic modification mechanisms involved in keloid: current status and prospect

Ren

Hou

et al. 2020

Clin Epigenet

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Keloid, a common dermal fibroproliferative disorder, is benign skin tumors characterized by the aggressive fibroblasts proliferation and excessive accumulation of extracellular matrix. However, common therapeutic approaches of keloid have limited effectiveness, emphasizing the momentousness of developing innovative mechanisms and therapeutic strategies. Epigenetics, representing the potential link of complex interactions between genetics and external risk factors, is currently under intense scrutiny. Accumulating evidence has demonstrated that multiple diverse and reversible epigenetic modifications, represented by DNA methylation, histone modification, and non-coding RNAs (ncRNAs), play a critical role in gene regulation and downstream fibroblastic function in keloid. Importantly, abnormal epigenetic modification manipulates multiple behaviors of keloid-derived fibroblasts, which served as the main cellular components in keloid skin tissue, including proliferation, migration, apoptosis, and differentiation. Here, we have reviewed and summarized the present available clinical and experimental studies to deeply investigate the expression profiles and clarify the mechanisms of epigenetic modification in the progression of keloid, mainly including DNA methylation, histone modification, and ncRNAs (miRNA, lncRNA, and circRNA). Besides, we also provide the challenges and future perspectives associated with epigenetics modification in keloid. Deciphering the complicated epigenetic modification in keloid is hopeful to bring novel insights into the pathogenesis etiology and diagnostic/therapeutic targets in keloid, laying a foundation for optimal keloid ending.

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Section: Conclusion and Future Perspectivesmentioning

confidence: 92%

Epigenetic modification mechanisms involved in keloid: current status and prospect

Ren

Hou

et al. 2020

Clin Epigenet

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“…The latter, therefore, might play a fundamental part in inhibiting keloid fibroblast proliferation. 38 A significant increase in collagen types I and III mRNA were found in the perilesional areas of keloid scars as compared with extralesional and intralesional sites in both in vivo and in vitro samples. 39 This suggests that keloid fibroblasts may have heterogeneous activity levels in vitro and in different parts of the keloid.…”

Section: New Candidatesmentioning

confidence: 89%

“…The latter, therefore, might play a fundamental part in inhibiting keloid fibroblast proliferation. 38 …”

Section: New Candidatesmentioning

confidence: 99%

The role of pharmacogenetics in keloid scar treatment: A literature review

Searle

Ali

Al‐Niaimi

2020

Scars, Burns & Healing

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Background: The pathophysiology of keloid scars is still not fully understood and a universally reliable effective treatment has not been identified. Pharmacogenetics explores how drug response to a particular therapy can relate to genetic variations. Purpose: To investigate how pharmacogenetics could be applied to keloid scars and the relevance of this to clinical practice. Methods: We reviewed the literature and discuss our current knowledge of pharmacogenomics in the treatment of keloid scars. A literature search was performed using the terms ‘Pharmacogenetics’, ‘Pharmacogenomics’, ‘Keloid’ and ‘Scar’. We searched the PubMed, MEDLINE and EMBASE databases to find the relevant articles. Only articles in English were chosen. The level of evidence was evaluated and selected accordingly listing the studies with the highest level of evidence first. Results: Treatments including corticosteroid injections and 5-fluorouracil can be effective in some patients, but less so in others. Polymorphisms of the glucocorticoid receptor and variants of CCL2, YAP1, miR-21-5p and NF-κβ might be responsible for different responses to treatments used in keloid scars such as 5-fluorouracil. Small molecule inhibitors might be utilised to target other implicated genes. Conclusion: Pharmacogenetics aims to produce the most efficacious patient outcomes while reducing adverse effects. Understanding the pharmacogenetics of keloid scars could lead to a new era of personalised medicine in the treatment of keloid scars. At present, there is some evidence (level 3b/4) to suggest genetic variations that are responsible to drug response in keloids, but further research in this field is required. Lay summary The varied response to similar therapeutic treatments in keloids has prompted the consideration of the role of genetic variants on response in the form of pharmacogenetics. Pharmacogenetics refers to drugs and their metabolism and action based on genetic influences. The ideal scenario would involve the selection of treatment based on the individual’s specific genetic variants to ensure maximum efficacy with minimal toxicity. Some evidence currently points to genetic variations in some keloid patients that might be of relevance to the treating clinician.

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“…No satisfactory treatment strategy has been developed, primarily because of the high recurrence rate of keloids, which can reach up to 70-80% post-excision (5,6). Extensive research has indicated that keloid development is complex and involves alterations in non-coding RNAs, dNA methylation and histone modification (7)(8)(9); however, the precise pathological mechanisms underlying how keloid formation and progression are initiated and regulated remain unknown, which has hindered the development of novel therapeutic strategies.…”

Section: Introductionmentioning

confidence: 99%

circNRIP1 facilitates keloid progression via FXR1‑mediated upregulation of miR‑503‑3p and miR‑503‑5p

et al. 2021

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circular nuclear receptor interacting protein 1 (circNRIP1) is implicated in tumor initiation and progression; however, the underlying mechanism of keloid progression is unclear. To the best of our knowledge, the present study is the first to characterize the contribution of circNRIP1 to keloid progression and evaluate the potential underlying molecular mechanisms using keloid-derived fibroblasts. The expression profile of circNRIP1 was confirmed in keloid tissue. The contribution of circNRIP1 to keloid progression was investigated via loss-of-function assays. Furthermore, the molecular mechanism by which circNRIP1 contributes to pre-microRNA (miR)-503 maturation through blocking Fbxo4-mediated Fragile-X mental retardation 1 (FXR1) ubiquitination was verified. Finally, the biological functions of FXR1, miR-503-3p, and miR-503-5p in keloid-derived fibroblast proliferation, apoptosis and extracellular matrix accumulation were confirmed. circNRIP1 was highly expressed in keloid tissue and keloid-derived fibroblasts. Functional analysis showed that circNRIP1 knockdown successfully blocked the proliferation and expression of extracellular matrix-associated proteins while increasing the rate of apoptosis in keloid-derived fibroblasts. Mechanistically, circNRIP1 maintained FXR1 stability by impeding Fbxo4-mediated FXR1 ubiquitination and degradation. Additionally, FXR1 increased the abundance of miR-503-3p and miR-503-5p by contributing to pre-miR-503 maturation. Knockdown of FXR1, miR-503-3p and miR-503-5p also inhibited proliferation and extracellular matrix accumulation in keloid-derived fibroblasts and increased levels of cell apoptosis. collectively, the present study confirmed that circNRIP1 contributed to pre-miR-503 maturation via blocking Fbxo4-mediated FXR1 ubiquitination and degradation, which facilitates keloid progression. These results indicate that circNRIP1 has potential as a novel therapeutic target for the control and/or treatment of keloids.

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Inhibition of microRNA-21-5p reduces keloid fibroblast autophagy and migration by targeting PTEN after electron beam irradiation

Cited by 27 publications

References 34 publications

Epigenetic modification mechanisms involved in keloid: current status and prospect

Epigenetic modification mechanisms involved in keloid: current status and prospect

The role of pharmacogenetics in keloid scar treatment: A literature review

circNRIP1 facilitates keloid progression via FXR1‑mediated upregulation of miR‑503‑3p and miR‑503‑5p

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