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qRT-PCR analysis of expression levels of 2 groups of ceRNA networks: EGFR (A)/miR-370-3p (B)/lnc-GLB1L-1 (C) and ITGB5 (D)/miR-204 (E)/lnc-CASP9-3 (F). *, P<0.05; ***, P<0.001. ceRNA, competing endogenous RNA.
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Background:
Keloid is an excessive fibrosis disease caused by the abnormal proliferation of collagen fibers following trauma. Previous studies have shown that genetic factors have been considered to play important roles in keloid formation. This study is aimed to investigate the regulatory network of messenger RNAs (mRNAs) microRNAs (miRNAs) and l...
Context in source publication
Context 1
... chose 2 groups of ceRNA network: EGFR/miR-370-3p/lnc-GLB1L-1 and ITGB5/miR-204/lnc-CASP9-3 to perform qRT-PCR validation using samples from another 10 patients with keloid and 9 of nearby normal tissue. As shown in Figure 7, the expression of all of the selected ceRNAs was coincident with the result of RNA-seq, which confirmed the accuracy of sequencing. In the first ceRNA network: EGFR and lnc-GLB1L-1 was downregulated, miR-370-3p was upregulated in keloid tissue. ...
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Citations
... The miRSNP rs188493331-miRNA-302e/302a-3p/20b-5p-LAMA3-focal adhesion regulatory axis in HS and keloids Among the signaling pathways we examined, the focal adhesion signaling pathway emerged as a pivotal player in the development of HS and keloids. [20][21][22] Within this pathway, we identified 39 central proteincoding genes, ten of which contained miRSNP loci in their 3′ UTR regions. Notably, LAMA3, ITGAV, and COL1A1 stood out as particularly susceptible to miRNA regulation. ...
Background
Our study aims to delineate the miRSNP–microRNA–gene–pathway interactions in the context of hypertrophic scars (HS) and keloids.
Materials and Methods
We performed a computational biology study involving differential expression analysis to identify genes and their mRNAs in HS and keloid tissues compared to normal skin, identifying key hub genes and enriching their functional roles, comprehensively analyzing microRNA‐target genes and related signaling pathways through bioinformatics, identifying MiRSNPs, and constructing a pathway‐based network to illustrate miRSNP‐miRNA‐gene‐signaling pathway interactions.
Results
Our results revealed a total of 429 hub genes, with a strong enrichment in signaling pathways related to proteoglycans in cancer, focal adhesion, TGF‐β, PI3K/Akt, and EGFR tyrosine kinase inhibitor resistance. Particularly noteworthy was the substantial crosstalk between the focal adhesion and PI3K/Akt signaling pathways, making them more susceptible to regulation by microRNAs. We also identified specific miRNAs, including miRNA‐1279, miRNA‐429, and miRNA‐302e, which harbored multiple SNP loci, with miRSNPs rs188493331 and rs78979933 exerting control over a significant number of miRNA target genes. Furthermore, we observed that miRSNP rs188493331 shared a location with microRNA302e, microRNA202a‐3p, and microRNA20b‐5p, and these three microRNAs collectively targeted the gene LAMA3, which is integral to the focal adhesion signaling pathway.
Conclusions
The study successfully unveils the complex interactions between miRSNPs, miRNAs, genes, and signaling pathways, shedding light on the genetic factors contributing to HS and keloid formation.
... The concept of competitive endogenous RNA (ceRNA) was initially proposed by Salmena et al. [16]. Importantly, in the ceRNA hypothesis, lncRNAs act as miRNA sponges to inhibit miRNA function and regulate mRNA expression [17]. Some previous studies have investigated PCOS-associated lncRNA-miRNA-mRNA ceRNA triple networks between follicular fluid and granulosa cells [18][19][20]. ...
Objective
Women who are of reproductive age can suffer from polycystic ovary syndrome (PCOS), an endocrine disorder. Anovulatory infertility is mostly caused by aberrant follicular development, which is seen in PCOS patients. Due to the dysfunction of reproductive and endocrine function in PCOS patients, assisted reproduction treatment is one of the main means to obtain clinical pregnancy for PCOS patients. Long non-coding RNA (lncRNA) as a group of functional RNA molecules have been found to participate in the regulation of oocyte function, hormone metabolism, and proliferation and apoptosis of granulosa cells. In this study, we investigated the role of lncRNAs in follicular fluid-derived exosomes and the underlying mechanism of lncRNA LIPE-AS1.
Methods
We used RNA sequencing to analyze the lncRNA profiles of follicular fluid-derived exosomes in PCOS patients and controls. RT-qPCR was performed to detect the expression levels of these lncRNAs in control (n = 30) and PCOS (n = 30) FF exosome samples. Furthermore, we validated the performance of lncRNA LIPE-AS1 in oocyte maturation by in vitro maturation (IVM) experiments in mouse and steroid metabolism in granulosa cells.
Results
We found 501 lncRNAs were exclusively expressed in the control group and another 273 lncRNAs were found to be specifically expressed in the PCOS group. LncRNA LIPE-AS1, highly expressed in PCOS exosomes, was related to a poor oocyte maturation and embryo development in PCOS patients. Reduced number of MII oocytes were observed in the LIPE-AS1 group by in vitro maturation (IVM) experiments in mouse. LIPE-AS1 was also shown to modulate steroid metabolism and granulosa cell proliferation and apoptosis by LIPE-AS1/miR-4306/LHCGR axis.
Conclusion
These findings suggested that the increased expression of LIPE-AS1, facilitated by follicular fluid exosomes, had a significant impact on both oocyte maturation and embryo development. We demonstrated the ceRNA mechanism involving LIPE-AS1, miR-4306, and LHCGR as a regulator of hormone production and metabolism. These findings indicate that LIPE-AS1 is essential in PCOS oocyte maturation and revealed a ceRNA network of LIPE-AS1 and provided new information on abnormal steroid metabolism and oocyte development in PCOS.
... lncRNA DLEU2 and lncRNA H19) and circRNAs (e.g. hsa_circ_0057452 and hsa_circ_0007482) [8][9][10]. Zhong et al. detected 264 significantly altered miRNAs in keloid and revealed that these miRNAs were associated with mitogen-activated protein kinase (MAPK) and hypoxia inducible factor-1 (HIF-1) signaling pathway activity based on enrichment analysis [11]. ...
Keloids are a fibrotic disease caused by an excessive accumulation of extracellular matrix in the dermis; they have neoplasia-like properties of aggressive growth and high posttreatment recurrence rates. Therefore, it is imperative to gain additional insight into the pathobiology of keloid formation. Single-cell RNA sequencing (scRNA-seq) technology has brought data-driven innovation to understanding the pathogenesis of keloids by breaking the limitations of traditional sequencing technologies to resolve cell composition and to distinguish functional cell subtypes at an unprecedented resolution. The present review aims to cover the application of scRNA-seq technology in keloids and its exploratory findings, including the depiction of the cellular landscape of keloids, fibroblast heterogeneity, the lineage development of Schwann cells and the mesenchymal-activation phenomenon of endothelial cells. Furthermore, scRNA-seq records the transcriptional profiles of fibroblasts and immune cells in a more refined manner, and this gene expression information provides excellent material for inferring intercellular communication networks and lays an important theoretical foundation for future studies.
... Keloids and hypertrophic scars are unpredictable fibroproliferative disorders of dermal tissue following skin injury. [1,2,5]. The relevance and complexity of studying the mechanisms of pathogenesis of the formation of skin scars is also evidenced by the fact that even at the present stage there is no single international classification of scars, as well as their prognostic indicators. ...
The frequency of complications associated with the use of cosmetic invasive interventions to rejuvenate and correct the shape of various parts of the face requires a deep study of the causes of keloid scarring induction. The paper presents an analysis of clinical material in the age aspect, depending on gender and topography of skin lesions. It was noted that in men, injuries are more often associated with burn injuries of the extremities. It has been established that complications of facial skin regeneration are more often observed in women aged 35 to 65 years, often against the background of the use of low-quality invasive materials and in patients with a history of keloid scars.
... Although microarray and RNA-Seq studies have identified several lncRNAs that are increased or decreased in keloids, and some of these lncRNA functions have previously been studied, [22][23][24][25] the understanding of the function of lncRNAs in keloid formation is still limited. In this study, we identified an lncRNA, DEIK, which was decreased in keloid fibroblasts ( Figure 2c). ...
Background
Keloids represent one extreme of aberrant dermal wound healing and are characterized by fibroblast hyperproliferation and excessive deposition of extracellular matrix. Genetics is a major factor for predisposition to keloids and genome-wide association study has identified a single-nucleotide polymorphism (SNP) rs873549 at 1q41 as a susceptibility locus. The SNP rs873549, and the SNPs in strong linkage disequilibrium (LD) with rs873549, may be involved in keloid development. However, the functional significance of these SNPs in keloid pathogenesis remains elusive.
Objectives
To investigate the function and mechanism of SNP rs873549 and the SNPs in strong LD with rs873549 in keloids.
Methods
SNPs in strong LD with rs873549 were analysed using Haploview. The expression levels of the genes near the susceptibility locus were analysed using quantitative real-time polymerase chain reaction. The interaction between rs1348270-containing enhancer and the long noncoding RNA down expressed in keloids (DEIK) (formerly RP11-400N13.1) promoter in fibroblasts was investigated using chromosome conformation capture. The enhancer activity of the rs1348270 locus was evaluated using luciferase reporter assay. Knockdown experiments were used to explore the function of DEIK in keloids. RNA-Seq was performed to investigate the mechanism by which DEIK regulates the expression of collagens POSTN and COMP.
Results
rs1348270, an enhancer-located SNP in strong LD with rs873549, mediated looping with the promoter of DEIK. The risk variant was associated with decreased enhancer–promoter interaction and DEIK down-expression in keloids. Mechanistically, downregulation of DEIK increased the expression of collagens POSTN and COMP through upregulating BMP2. Furthermore, correlation analysis revealed that DEIK expression was inversely correlated with BMP2, POSTN and COMP expression in both keloid and normal fibroblasts.
Conclusions
Our findings suggest that the risk variant rs1348270 is located in an enhancer and is associated with the downregulation of DEIK in keloids, and that downregulation of DEIK increases the expression of collagens POSTN and COMP through BMP2 in keloid fibroblasts. These findings will help to provide a more thorough understanding of the role played by genetic factors in keloid development and may lead to new strategies for screening and therapy in keloid-susceptible populations.
... As one of the "goods" delivered by exosomes, lncRNAs potentially play various important regulatory roles in the pathogenesis of PCOS (Tu et al., 2021). Importantly, in the ceRNA hypothesis, lncRNAs are called miRNA sponges because they can bind miRNAs and prevent miRNA function, and lncRNAs take advantage of this by playing a regulatory role (Tan et al., 2015;Duan et al., 2020). Therefore, we need to further explore the relationship between the lncRNAs of exosomes and the miRNA and mRNA in granulosa cells to understand the disease progression of PCOS. ...
Polycystic ovary syndrome (PCOS), a common and frustrating syndrome in women of reproductive age, is characterized by symptoms including hyperandrogenemia, ovulation dysfunction, and polycystic ovaries. The role of competitive endogenous RNA (ceRNA) networks is receiving increasing attention and has been reported in multiple complicated diseases, such as various carcinomas, endometriosis, and tubal factor infertility. However, the association of ceRNA networks with the pathogenesis of PCOS remains unclear. This study aimed to construct a ceRNA network orchestrated by exosomal lnRNA and circRNA in PCOS. We screened RNA data of 34 samples from the Gene Expression Omnibus (GEO) database for differentially expressed lncRNAs (DELs), miRNAs (DEMs), mRNAs (DEGs), and circRNA associated with the progression of PCOS (PCOS, n = 17 vs. normal, n = 17). A protein–protein interaction (PPI) network, gene set enrichment analysis (GSEA), and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted. Importantly, the function of the ceRNA network was explored using GO and KEGG enrichment analyses. We identified 46 DELs (25 upregulated and 21 downregulated), 31 DEMs (20 upregulated and 11 downregulated), 165 DEGs (52 upregulated and 113 downregulated), and 1 differentially expressed circRNA. The PPI network had 79 nodes and 112 edges. The GSEA results showed that these genes were mainly related to oxidative phosphorylation; TNF signaling pathways; and valine, leucine, and isoleucine degradation. GO and KEGG analyses revealed that the DEGs were significantly enriched in lipid metabolism, peroxisome proliferator-activated receptor (PPAR) signaling pathways, and fatty acid metabolism. Additionally, we constructed a novel PCOS-associated lncRNA–miRNA–mRNA ceRNA triple network and a circRNA-related network. Thereafter, we described the potential roles played by follicular fluid exosomes in PCOS. Our present study describes the molecular pathogenesis of PCOS in human ovarian granulosa cells at the post-transcriptional level, which provides new insights for the clinical diagnosis and treatment of PCOS and further scientific research.
... In this study, miR-188-5p was also downregulated in keloids, and miR-188-5p overexpression could suppress the biological activities of keloid cells. LncRNAs can participate in the regulation of diseases through a variety of pathways, the most common of which is the ceRNA mechanism, namely, the targeting of lncRNAs to miRNAs, thereby regulating the expression of downstream molecules [41]. Besides, a large number of studies confirmed the interrelation between miR-188-5p and lncRNA in a variety of diseases. ...
Keloid is a common dermis tumor, occurring repeatedly, affecting the quality of patients’ life. Long non-coding RNAs (lncRNAs) have crucial regulatory capacities in skin scarring formation and subsequent scar carcinogenesis. The intention of this study was to investigate the mechanism and function of GNAS antisense-1 (GNAS-AS1) in keloids. Clinical samples were collected to evaluate the expression of GNAS-AS1, RUNX2, and miR-188-5p by qRT-PCR. The proliferation, migration, and invasion of HKF cells were detected by CCK-8, wound healing, and Transwell assays. The expression levels of mRNA and protein were examined through qRT-PCR and Western blot assay. Luciferase reporter assay was used to identify the binding relationship among GNAS-AS1, miR-188-5p, and Runt-related transcription factor 2 (RUNX2). GNAS-AS1 and RUNX2 expressions were remarkably enhanced, and miR-188-5p expression was decreased in keloid clinical tissues and HKF cells. GNAS-AS1 overexpression promoted cells proliferation, migration, and invasion, while GNAS-AS1 knockdown had the opposite trend. Furthermore, overexpression of GNAS-AS1 reversed the inhibitory effect of 5-FU on cell proliferation, migration, and invasion. MiR-188-5p inhibition or RUNX2 overexpression could enhance the proliferation, migration, and invasion of HKF cells. GNAS-AS1 targeted miR-188-5p to regulate RUNX2 expression. In addition, the inhibition effects of GNAS-AS1 knockdown on HKF cells could be reversed by inhibition of miR-188-5p or overexpression of RUNX2, while RUNX2 overexpression eliminated the suppressive efficaciousness of miR-188-5p mimics on HKF cells growth. GNAS-AS1 knockdown could regulate the miR-188-5p/RUNX2 signaling axis to inhibit the growth and migration in keloid cells. It is suggested that GNAS-AS1 may become a new target for the prevention and treatment of keloid.
... Another study identified a total of 319 keloid-specific lncRNAs using RNA-seq and miRNA-seq (Duan et al., 2020). The study also identified two competing endogenous RNAs (ceRNA) network of mRNA/miRNA/lncRNA in the regulation of the actin cytokeleton pathway. ...
Keloids are pathologic wound healing conditions caused by fibroblast hyperproliferation and excess collagen deposition following skin injury or irritation, which significantly impact patients by causing psychosocial and functional distress. Extracellular matrix (ECM) deposition and human fibroblast proliferation represents the main pathophysiology of keloid. Long non-coding RNAs (LncRNAs) play important roles in many biological and pathological processes, including development, differentiation and carcinogenesis. Recently, accumulating evidences have demonstrated that deregulated lncRNAs contribute to keloids formation. The present review summarizes the researches of deregulated lncRNAs in keloid. Exploring lncRNA-based methods hold promise as new effective therapies against keloid.
... The expression of lncRNA ATB is positively KFB keloid fibroblast cells, EMT endothelial-mesenchymal transition, ECM extracellular matrix associated with the self-secretion level of TGF-β2, which is accomplished by downregulating tumor-suppressive miR-200c and subsequently acting on zinc finger protein 217 (ZNF217), an agitator associated with TGF-β [153]. In keloid RNA sequencing and miRNA sequencing, a total of 319 lncRNAs were identified, and two pairs of competing endogenous RNA networks regulating the actin cytoskeleton were constructed: lnc-GLB1L-1/miR-370-3p/EGFR and lnc-CASP9-3/miR-204/ITGB5 [167]. Almost all of these lncRNAs with abnormal expression in keloids have been extensively scrutinized in tumors, and their mechanisms have been confirmed in multiple cancers [160, N/A not available, miR microRNA,TM4SF1 transmembrane 4 L six family member 1, SMAD3 SMAD family member 3, TGF-βR1 transforming growth factor beta receptor 1, IRF5 interferon regulatory factor 5, CDK6 cyclin-dependent kinase 6, GAB1 growth factor receptor-bound protein 2-associated binding protein 1, FOXF1 forkhead box F1, PHLPP2 PH domain and leucine-rich repeat protein phosphatase 2, MMP-2 matrix metallopeptidase 2, RUNX2 RUNX family transcription factor 2, NR2F2 nuclear receptor subfamily 2 group F member 2, COLIα1 collagen type I alpha 1 chain, FGF2 fibroblast growth factor 2, ZNF217 zinc finger protein 217, EGR1 early growth response 1, ITGβ5 integrin subunit beta 5, VEGF vascular endothelial growth factor, FasL Fas ligand, PTEN phosphatase and tensin homolog, FN fibronectin, ZEB2 zinc finger E-box binding homeobox 2, MC1R melanocortin 1 receptor, BCL2 B-cell lymphoma-2, HIF-1α hypoxia inducible factor 1 subunit alpha inhibitor, EGFR epidermal growth factor receptor, CCND1 cyclinD1, EPAC1 exchange protein directly activated by CAMP 1, EIF3A eukaryotic translation Initiation factor 3 subunit A 161,168]. ...
Keloid scarring is a kind of pathological healing manifestation after skin injury and possesses various tumor properties, such as the Warburg effect, epithelial-mesenchymal transition (EMT), expression imbalances of apoptosis-related genes and the presence of stem cells. Abnormal expression of tumor signatures is critical to the initiation and operation of these effects. Although previous experimental studies have recognized the potential value of a single or several tumor biomolecules in keloids, a comprehensive evaluation system for multiple tumor signatures in keloid scarring is still lacking. This paper aims to summarize tumor biomolecules in keloids from the perspectives of liquid biopsy, genetics, proteomics and epigenetics and to investigate their mechanisms of action and feasibility from bench to bedside. Liquid biopsy is suitable for the early screening of people with keloids due to its noninvasive and accurate performance. Epigenetic biomarkers do not require changes in the gene sequence and their reversibility and tissue specificity make them ideal therapeutic targets. Nonetheless, given the ethnic specificity and genetic predisposition of keloids, more large-sample multicenter studies are indispensable for determining the prevalence of these signatures and for establishing diagnostic criteria and therapeutic efficacy estimations based on these molecules.
... Several investigators have found a clear relationship between snoRNAs and cancer (Askarian-Amiri et al., 2011;Li et al., 2015). Numerous lncRNAs have been shown to regulate miRs in keloid formation through RNA sponging (Duan et al., 2020), so we speculated that snoRNAs might be regulators. ...
The skin is an organ that protects against injury and infection but can be damaged easily. Wound healing is a subtle balance which, if broken, can lead to keloid formation. Small noncoding (nc) RNAs can be of “housekeeping,” for example, ribosomal RNAs and transfer RNAs, or “regulatory,” for example, microRNAs (miRNAs or miRs), small nucleolar RNAs (snoRNAs), and P-element–induced Wimpy testis (PIWI)-interacting RNA (piRNA) types. We examined five types of small ncRNAs [miR, piRNA, snoRNA, small nuclear (sn) RNA, and repeat-associated small interfering RNA (rasiRNA)] in keloid skin tissue (KST) using sequencing and real-time reverse transcription-quantitative polymerase chain reaction. All comparisons were made in relation to expression in normal skin tissue (obtained by abdominoplasty). The expression of three piRNAs was upregulated, and the expression of six piRNAs was downregulated in KST. The expression of 12 snoRNAs was upregulated, and the expression of two snoRNAs was downregulated in KST. The expression of two snRNAs was downregulated in KST. The expression of 18 miRs was upregulated, and the expression of three miRNAs was downregulated in KST. The expression of one rasiRNA was upregulated, and the expression of one rasiRNA was downregulated in KST. We revealed the differential expression of small ncRNAs in KST, which may aid the development of new treatment for keloids.
