Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2021

Open Access 01-12-2021 | Research

Identification and functional analysis of a three-miRNA ceRNA network in hypertrophic scars

Authors: Zewei Zhang, Xin Huang, Jiahao Yang, Shuchen Gu, Yixuan Zhao, Yunhan Liu, Yimin Khoong, Shuqi Wang, Shenying Luo, Tao Zan, Guangshuai Li

Published in: Journal of Translational Medicine | Issue 1/2021

Login to get access

Abstract

Background

Hypertrophic scar (HTS) is a fibrotic disorder of skins and may have repercussions on the appearance as well as functions of patients. Recent studies related have shown that competitive endogenous RNA (ceRNA) networks centering around miRNAs may play an influential role in HTS formation. This study aimed to construct and validate a three-miRNA (miR-422a, miR-2116-3p, and miR-3187-3p) ceRNA network, and explore its potential functions.

Methods

Quantitative real‑time PCR (qRT‑PCR) was used to compare expression levels of miRNAs, lncRNAs, and genes between HTS and normal skin. Target lncRNAs and genes of each miRNA were predicted using starBase as well as TargetScan database to construct a distinct ceRNA network; overlapping target lncRNAs and genes of the three miRNAs were utilized to develop a three-miRNA ceRNA network. For every network, protein–protein interaction (PPI) network analysis was performed to identify its hub genes. For each network and its hub genes, Gene Oncology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were conducted to explore their possible functions.

Results

MiR-422a, miR-2116-3p, and miR-3187-3p were all downregulated in HTS tissues and fibroblasts. MiR-422a-based ceRNA network consisted of 101 lncRNAs with 133 genes; miR-2116-3p-centered ceRNA network comprised 85 lncRNAs and 978 genes; miR-3187-3p-derived ceRNA network encompassed 84 lncRNAs as well as 1128 genes. The three-miRNA ceRNA network included 2 lncRNAs with 9 genes, where MAPK1, FOSL2, ABI2, KPNA6, CBL, lncRNA-KCNQ1OT1, and lncRNA-EBLN3P were upregulated. According to GO and KEGG analysis, these networks were consistently related to ubiquitination. Three ubiquitination-related genes (CBL, SMURF2, and USP4) were upregulated and negatively correlated with the expression levels of the three miRNAs in HTS tissues.

Conclusions

This study identified a three-miRNA ceRNA network, which might take part in HTS formation and correlate with ubiquitination.
Literature
1.
Finnerty CC, Jeschke MG, Branski LK, Barret JP, Dziewulski P, Herndon DN. Hypertrophic scarring: the greatest unmet challenge after burn injury. Lancet. 2016;388:1427–36.CrossRefPubMedPubMedCentral
2.
Chen L, Li J, Li Q, Yan H, Zhou B, Gao Y, et al. Non-coding RNAs: the new insight on hypertrophic scar. J Cell Biochem. 2017;118:1965–8.CrossRefPubMed
3.
Li L, Han W, Chen Y, Chen Y. MiR-3613-3p inhibits hypertrophic scar formation by down-regulating arginine and glutamate-rich 1. Mol Cell Biochem. 2021;476:1025–36.CrossRefPubMed
4.
Wang R, Zhang S, Chen X, Li N, Li J, Jia R, et al. CircNT5E Acts as a Sponge of miR-422a to Promote Glioblastoma Tumorigenesis. Cancer Res. 2018;78:4812–25.CrossRefPubMed
5.
Chen W, Zhao W, Yang A, Xu A, Wang H, Cong M, et al. Integrated analysis of microRNA and gene expression profiles reveals a functional regulatory module associated with liver fibrosis. Gene. 2017;636:87–95.CrossRefPubMed
6.
Wu M, Wu W, Ding J, Yang J. LINC01433/miR-2116-3p/MYC feedback loop promotes cell proliferation, migration, and the epithelial-mesenchymal transition in breast cancer. Cancer Biother Radiopharm. 2019;34:388–97.CrossRefPubMed
7.
Xiao M, Zou X, Li B, Zhang B. Long non-coding RNA H19 promotes the proliferation, migration and invasion while inhibits apoptosis of hypertrophic scarring fibroblasts by targeting miR-3187-3p/GAB1 axis. Burns. 2021;47:654–64.CrossRefPubMed
8.
Guo L, Xu K, Yan H, Feng H, Wang T, Chai L, et al. MicroRNA expression signature and the therapeutic effect of the microRNA-21 antagomir in hypertrophic scarring. Mol Med Rep. 2017;15:1211–21.CrossRefPubMedPubMedCentral
9.
Tu L, Huang Q, Fu S, Liu D. Aberrantly expressed long noncoding RNAs in hypertrophic scar fibroblasts in vitro: a microarray study. Int J Mol Med. 2018;41:1917–30.PubMedPubMedCentral
10.
Yang Z, Xiao Z, Guo H, Fang X, Liang J, Zhu J, et al. Novel role of the clustered miR-23b-3p and miR-27b-3p in enhanced expression of fibrosis-associated genes by targeting TGFBR3 in atrial fibroblasts. J Cell Mol Med. 2019;23:3246–56.CrossRefPubMedPubMedCentral
11.
Zhao Y, Zhang F, Pan Z, Luo H, Liu K, Duan X. LncRNA NR_003923 promotes cell proliferation, migration, fibrosis, and autophagy via the miR-760/miR-215-3p/IL22RA1 axis in human Tenon’s capsule fibroblasts. Cell Death Dis. 2019;10:594.CrossRefPubMedPubMedCentral
12.
Xu X, Khoong YM, Gu S, Huang X, Ren J-Y, Gu Y-H, et al. Investigating the potential of LSKL peptide as a novel hypertrophic scar treatment. Biomed Pharmacother. 2020;124:109824.CrossRefPubMed
13.
Amini-Nik S, Yousuf Y, Jeschke MG. Scar management in burn injuries using drug delivery and molecular signaling: current treatments and future directions. Adv Drug Deliv Rev. 2018;123:135–54.CrossRefPubMed
14.
Zhu Z, Hou Q, Li M, Fu X. Molecular mechanism of myofibroblast formation and strategies for clinical drugs treatments in hypertrophic scars. J Cell Physiol. 2020;235:4109–19.CrossRefPubMed
15.
Fang F, Huang R-L, Zheng Y, Liu M, Huo R. Bone marrow derived mesenchymal stem cells inhibit the proliferative and profibrotic phenotype of hypertrophic scar fibroblasts and keloid fibroblasts through paracrine signaling. J Dermatol Sci. 2016;83:95–105.CrossRefPubMed
16.
17.
Zhou Z, Lin Z, He Y, Pang X, Wang Y, Ponnusamy M, et al. The long noncoding RNA D63785 regulates chemotherapy sensitivity in human gastric cancer by targeting miR-422a. Mol Ther Nucleic Acids. 2018;12:405–19.CrossRefPubMedPubMedCentral
18.
Liang H, Wang R, Jin Y, Li J, Zhang S. MiR-422a acts as a tumor suppressor in glioblastoma by targeting PIK3CA. Am J Cancer Res. 2016;6:1695–707.PubMedPubMedCentral
19.
Wei W-T, Nian X-X, Wang S-Y, Jiao H-L, Wang Y-X, Xiao Z-Y, et al. miR-422a inhibits cell proliferation in colorectal cancer by targeting AKT1 and MAPK1. Cancer Cell Int. 2017;17:91.CrossRefPubMedPubMedCentral
20.
Zou Y, Chen Y, Yao S, Deng G, Liu D, Yuan X, et al. MiR-422a weakened breast cancer stem cells properties by targeting PLP2. Cancer Biol Ther. 2018;19:436–44.CrossRefPubMedPubMedCentral
21.
Shi J, Wang H, Guan H, Shi S, Li Y, Wu X, et al. IL10 inhibits starvation-induced autophagy in hypertrophic scar fibroblasts via cross talk between the IL10-IL10R-STAT3 and IL10-AKT-mTOR pathways. Cell Death Dis. 2016;7:e2133.CrossRefPubMedPubMedCentral
22.
Sierra-Sánchez Á, Montero-Vilchez T, Quiñones-Vico MI, Sanchez-Diaz M, Arias-Santiago S. Current Advanced Therapies Based on Human Mesenchymal Stem Cells for Skin Diseases. Frontiers in cell and developmental biology. Front Cell Dev Biol; 2021;9. https://​pubmed.​ncbi.​nlm.​nih.​gov/​33768095/​
23.
Zhang Z, Liu C, Chen B, Tang W, Liu Z, Cao W, et al. Smad7 down-regulation via ubiquitin degradation mediated by Smurf2 in fibroblasts of hypertrophic scars in burned patients. Burns. 2021;47:1333–41.CrossRefPubMed
24.
Zhang J, Na S, Pan S, Long S, Xin Y, Jiang Q, et al. Inhibition of USP4 attenuates pathological scarring by downregulation of the TGF-β/Smad signaling pathway. Mol Med Rep. 2019;20:1429–35.PubMed
25.
Du S, Wang S, Zhang F, Lv Y. SKP2, positively regulated by circ_ODC1/miR-422a axis, promotes the proliferation of retinoblastoma. J Cell Biochem. 2020;121:322–31.CrossRefPubMed
26.
Inui N, Sakai S, Kitagawa M. Molecular Pathogenesis of pulmonary fibrosis, with focus on pathways related to TGF-β and the ubiquitin-proteasome pathway. Int J Mol Sci. 2021;22:6107.CrossRefPubMedPubMedCentral
27.
Jiang H, Liu H, Jiang B. Long non-coding RNA FALEC promotes colorectal cancer progression via regulating miR-2116-3p-targeted PIWIL1. Cancer Biol Ther. 2020;21:1025–32.CrossRefPubMedPubMedCentral
28.
Huang H, Yu X, Han X, Hao J, Zhao J, Bebek G, et al. Piwil1 regulates glioma stem cell maintenance and glioblastoma progression. Cell Rep. 2021;34:108522.CrossRefPubMedPubMedCentral
29.
Chen X, Li H-D, Bu F-T, Li X-F, Chen Y, Zhu S, et al. Circular RNA circFBXW4 suppresses hepatic fibrosis via targeting the miR-18b-3p/FBXW7 axis. Theranostics. 2020;10:4851–70.CrossRefPubMedPubMedCentral
30.
Yang G, Zhang T, Ye J, Yang J, Chen C, Cai S, et al. Circ-ITGA7 sponges miR-3187-3p to upregulate ASXL1, suppressing colorectal cancer proliferation. Cancer Manag Res. 2019;11:6499–509.CrossRefPubMedPubMedCentral
31.
Scheuermann JC, de Ayala Alonso AG, Oktaba K, Ly-Hartig N, McGinty RK, Fraterman S, et al. Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB. Nature. 2010;465:243–7.CrossRefPubMedPubMedCentral
32.
Shen W, Zhang Z, Ma J, Lu D, Lyu L. The ubiquitin proteasome system and skin fibrosis. Mol Diagn Ther. 2021;25:29–40.CrossRefPubMed
33.
Ucero AC, Bakiri L, Roediger B, Suzuki M, Jimenez M, Mandal P, et al. Fra-2-expressing macrophages promote lung fibrosis in mice. J Clin Invest. 2019;129:3293–309.CrossRefPubMedPubMedCentral
34.
Seidenberg J, Stellato M, Hukara A, Ludewig B, Klingel K, Distler O, et al. The AP-1 transcription factor fosl-2 regulates autophagy in cardiac fibroblasts during myocardial fibrogenesis. Int J Mol Sci. 2021;22:1861.CrossRefPubMedPubMedCentral
35.
Huang J, Maier C, Zhang Y, Soare A, Dees C, Beyer C, et al. Nintedanib inhibits macrophage activation and ameliorates vascular and fibrotic manifestations in the Fra2 mouse model of systemic sclerosis. Ann Rheum Dis. 2017;76:1941–8.CrossRefPubMed
36.
Chen X, Wang Z, Tong F, Dong X, Wu G, Zhang R. lncRNA UCA1 promotes gefitinib resistance as a ceRNA to target FOSL2 by sponging miR-143 in non-small cell lung cancer. Mol Ther Nucleic Acids. 2020;19:643–53.CrossRefPubMed
37.
Li Z, Niu H, Qin Q, Yang S, Wang Q, Yu C, et al. lncRNA UCA1 mediates resistance to cisplatin by regulating the miR-143/FOSL2-signaling pathway in ovarian cancer. Mol Ther Nucleic Acids. 2019;17:92–101.CrossRefPubMedPubMedCentral
38.
Yang F, Qin Y, Lv J, Wang Y, Che H, Chen X, et al. Silencing long non-coding RNA Kcnq1ot1 alleviates pyroptosis and fibrosis in diabetic cardiomyopathy. Cell Death Dis. 2018;9:1000.CrossRefPubMedPubMedCentral
Metadata
Title
Identification and functional analysis of a three-miRNA ceRNA network in hypertrophic scars
Authors
Zewei Zhang
Xin Huang
Jiahao Yang
Shuchen Gu
Yixuan Zhao
Yunhan Liu
Yimin Khoong
Shuqi Wang
Shenying Luo
Tao Zan
Guangshuai Li
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2021
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-021-03091-y

Other articles of this Issue 1/2021

Journal of Translational Medicine 1/2021 Go to the issue

Research

Niraparib exhibits a synergistic anti-tumor effect with PD-L1 blockade by inducing an immune response in ovarian cancer

Review

Pathophysiology of skeletal muscle disturbances in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Research

Gene alterations as predictors of radiation-induced toxicity in head and neck squamous cell carcinoma

Correction

Correction to: Total saponin from Anemone flaccida Fr. Schmidt abrogates osteoclast differentiation and bone resorption via the inhibition of RANKL-induced NF-κB, JNK and p38 MAPKs activation

Research

Improvement of urinary tract symptoms and quality of life in benign prostate hyperplasia patients associated with consumption of a newly developed whole tomato-based food supplement: a phase II prospective, randomized double-blinded, placebo-controlled study

Research

Combination of subtherapeutic anti-TNF dose with dasatinib restores clinical and molecular arthritogenic profiles better than standard anti-TNF treatment
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits