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

Zhang, Qiguo; Cai, Liangqi; Wang, Mian; Ke, Xiaoping; Zhao, Xiaoyan; Huang, Yijin

doi:10.1007/s00403-018-1847-3

Cited by 3 publications

(7 citation statements)

References 19 publications

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“…Through a multistage genome-wide association study in the Japanese population, Nakashima et al determined four new susceptibility loci (rs873549, rs1511412, rs940187, and rs8032158) to keloids in three chromosomal regions (1q41, 3q22.3-23, and 15q21.3) [ 89 ]. The findings of Zhang et al identified that a novel missense mutation in the CXCR1 gene existed in keloids and heightened CXCR1 expression was associated with keloid pathogenesis [ 90 ]. Interestingly, there is evidence suggesting that the pro allele of P53 Arg72Pro polymorphism increased genetic susceptibility for keloids in the Chinese population.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

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: 99%

Epigenetic modification mechanisms involved in keloid: current status and prospect

Ren

Hou

et al. 2020

Clin Epigenet

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“…However, the possibility of mutations caused by these genes cannot be completely ruled out because the current study is mainly focused on examining the promoter, exon and the connection region between exon and intron, and pathogenic mutations may be located in other non‐coding regions (such as introns or terminal genes). At present, it has been reported that somatic point mutations of the CXCR1 gene and the CDC2L1 gene were found in KD tissues 55,56 . A study showed that when compared to healthy control skin tissues, the expression of the CXCR1 gene was obviously elevated in keloid tissues, and a novel missense mutation was identified by the sequence analysis 55 .…”

Section: Genetic Susceptibility and Genetics Of Keloidsmentioning

confidence: 99%

Keloid: Genetic susceptibility and contributions of genetics and epigenetics to its pathogenesis

Liu

Yang

Song

et al. 2022

Experimental Dermatology

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Keloid, characterized by fibroproliferative disorders of the skin, can be developed in people of different genders, ages and ethnicities. Keloid can appear in any part of the body but are especially common on the earlobe, upper torso and triangular muscle. The genetic heterogeneity and susceptibility of KD (keloid) vary among different races and ethnicities. Studies have found that multiple loci on multiple chromosomes are associated with the pathogenesis of KD, and specific gene variants may also be involved. Despite multiple investigations attempting to uncover the aetiology of keloid formation, the genetic mechanism of keloid formation remains unknown. To establish a foundation for a better understanding of the genetics and epigenetics of keloids, we have evaluated and summarized current studies which are mostly related to heredity, genetic polymorphisms, predisposing gene, DNA methylation and non‐coding RNA. We also discussed the problems and potential of genetic and epigenetic investigations of keloids, with the goal of developing new therapeutic approaches to enhance the prognosis of keloid patients.

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“…a wound healing assay was used to analyze the migratory ability of HKFs. Briefly, the fibroblasts were seeded into 6-well culture plates at a density of 1x10 6 cells/well and transfected with si-runx2 or si-nc for 24 h at 37˚C. A scratch was created using a sterile 200-µl pipette tip in the cell monolayer upon the fibroblasts reaching 95-100% confluence.…”

Section: Reverse Transcription-quantitative Pcr (Rt-qpcr)mentioning

confidence: 99%

“…Briefly, HKFs were seeded into 6-well plates at a density of 1x10 6 cells/well and incubated for 12 h at 37˚C. Cells were transfected with si-Runx2 or si-NC for 24 h at 37˚C, subsequently harvested (300 x g; 5 min at 37˚C), washed with PBS and resuspended with 200 µl the Annexin V-PI binding buffer at a final density of 2x10 6 Statistical analysis. Statistical analysis was performed using GraphPad Prism version 8.0.1 software (GraphPad Software, inc.) and all data are presented as the mean ± Sd.…”

Section: Reverse Transcription-quantitative Pcr (Rt-qpcr)mentioning

confidence: 99%

“…To some extent, keloids exhibit invasive and immortal growth, similar to tumor tissues (4). Based on the rna-Seq analysis of keloid and normal skin samples, previous studies indicated that changes in the expression levels of pro-fibrotic genes are found to serve a significant role in Treatment of keloids through Runx2 siRNA-induced inhibition of the PI3K/AKT signaling pathway keloid formation (5,6). although various therapeutic modalities are used to treat keloids, such as local surgical resection combined with radiotherapy, laser treatments, cryotherapy and chemotherapy, the clinical effects remain unsatisfactory (7).…”

Section: Introductionmentioning

confidence: 99%

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Treatment of keloids through Runx2 siRNA‑induced inhibition of the PI3K/AKT signaling pathway

Ren

et al. 2020

Mol Med Rep

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Keloids are a skin fibroproliferative condition characterized by the hyperproliferation of fibroblasts and the excessive deposition of extracellular matrix (ECM) components. Previous studies have determined that Caveolin-1 controlled hyperresponsiveness to mechanical stimuli through Runt-related transcription factor 2 (Runx2) activation in keloids. However, the molecular mechanism of Runx2 regulating the pathological progression of keloids has not been elucidated. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that most of the differentially expressed genes (DEGs), including Runx2, were significantly enriched in the biological processes ‘Positive regulation of cell proliferation’, in the cellular components ‘Extracellular matrix’, in the molecular functions ‘Extracellular matrix structural constituents’ and in the KEGG ‘PI3K-Akt signaling pathway’. The aim of the present study was to investigate the expression levels of the Runx2 in human keloid tissues and primary human keloid fibroblasts (HKFs), and to determine the underlying molecular mechanisms involved in the fibrotic roles of Runx2 in keloid formation. Runx2 expression levels were analyzed in patient keloid tissues and HKFs using western blotting, reverse transcription-quantitative PCR (RT-qPCR) and immunofluorescence microscopy. Primary HKFs were transfected with a small interfering RNA (si) specifically targeting Runx2 (si-Runx2). Subsequently, Cell Counting Kit-8, wound healing and Transwell assays, flow cytometry, RT-qPCR and western blotting were applied to evaluate the proliferation, migration, apoptosis, ECM deposition and PI3K/AKT signaling pathway of HKFs, respectively. In addition, western blotting was also used to determine the expression levels of phosphorylated AKT and PI3K in HKFs. The results revealed that Runx2 expression levels were upregulated in keloid tissues and primary HKFs compared with the normal skin tissues and human normal fibroblasts. Following the transfection with si-Runx2, the proliferative and migratory abilities of HKFs were significantly reduced and the apoptotic rate was increased. The expression levels of type I, type III collagen, fibronectin, and α-smooth muscle actin were downregulated in si-Runx2-transfected cells, which was hypothesized to occur through following the downregulation of the phosphorylation levels of PI3K and AKT. In conclusion, the findings of the present study indicated that Runx2 silencing in HKFs might significantly inhibit the cell proliferation, migration and the expression levels of ECM-related proteins, and promote apoptosis via suppressing the PI3K/AKT signaling pathway. Thus, Runx2 siRNA treatment may reverse the pathological phenotype of keloids through the inhibition of PI3K/AKT signaling in patients.

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

Cited by 3 publications

References 19 publications

Epigenetic modification mechanisms involved in keloid: current status and prospect

Epigenetic modification mechanisms involved in keloid: current status and prospect

Keloid: Genetic susceptibility and contributions of genetics and epigenetics to its pathogenesis

Treatment of keloids through Runx2 siRNA‑induced inhibition of the PI3K/AKT signaling pathway

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