Induction of specific microRNAs inhibits cutaneous wound healing Journal Article
| Authors: | Pastar, I.; Khan, A. A.; Stojadinovic, O.; Lebrun, E. A.; Medina, M. C.; Brem, H.; Kirsner, R. S.; Jimenez, J. J.; Leslie, C.; Tomic-Canic, M. |
| Article Title: | Induction of specific microRNAs inhibits cutaneous wound healing |
| Abstract: | Chronic nonhealing wounds, such as venous ulcers (VUs), are a widespread and serious medical problem with high morbidity and mortality. The molecular pathology of VUs remains poorly understood, impeding the development of effective treatment strategies. Using mRNA expression profiling of VUs biopsies and computational analysis, we identified a candidate set of microRNAs with lowered target gene expression. Among these candidates, miR-16, -20a, -21, -106a -130a, and -203 were confirmed to be aberrantly overexpressed in a cohort study of 10 VU patients by quantitative PCR and in situ hybridizations. These microRNAs were predicted to target multiple genes important for wound healing, including early growth response factor 3, vinculin, and leptin receptor (LepR). Overexpression of the top up-regulated miRNAs, miR-21 and miR-130a, in primary human keratinocytes down-regulated expression of the endogenous LepR and early growth response factor 3. The luciferase reporter assay verified LepR as a direct target for miR-21 and miR-130a. Both miR-21 and miR-130a delayed epithelialization in an acute human skin wound model. Furthermore, in vivo overexpression of miR-21 inhibited epithelialization and granulation tissue formation in a rat wound model. Our results identify a novel mechanism in which overexpression of specific set of microRNAs inhibits wound healing, resulting in new potential molecular markers and targets for therapeutic intervention. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc. |
| Keywords: | adult; controlled study; human tissue; aged; aged, 80 and over; middle aged; unclassified drug; human cell; nonhuman; pathophysiology; polymerase chain reaction; animal cell; animals; mice; animal tissue; gene; gene targeting; gene overexpression; cohort studies; microrna; gene expression; gene expression profiling; skin biopsy; animal experiment; animal model; cohort analysis; gene function; keratinocyte; skin; wound healing; molecular marker; gene expression regulation; in situ hybridization; gene activation; messenger rna; dogs; gene identification; rat; in-vivo; down regulation; rats; epithelization; molecular biology; micrornas; disease models, animal; computer prediction; wound healing impairment; transcriptome; human skin; tissue; over-expression; rats, long-evans; quantitative study; chickens; computer analysis; granulation tissue; in-situ hybridization; human keratinocytes; leptin receptor; receptors, leptin; mrna expression; early growth response protein 1; multiple genes; microrna 21; quantitative pcr; vinculin; therapeutic intervention; computational analysis; cutaneous wounds; early growth; leptin receptors; luciferase reporter assays; target gene expression; tissue formation; venous ulcers; early growth response factor 3; microrna 106a; microrna 130a; microrna 16; microrna 203; microrna 20a; early growth response factor 3 gene; lepr gene |
| Journal Title: | Journal of Biological Chemistry |
| Volume: | 287 |
| Issue: | 35 |
| ISSN: | 0021-9258 |
| Publisher: | American Society for Biochemistry and Molecular Biology |
| Date Published: | 2012-08-24 |
| Start Page: | 29324 |
| End Page: | 29335 |
| Language: | English |
| DOI: | 10.1074/jbc.M112.382135 |
| PROVIDER: | scopus |
| PMCID: | PMC3436197 |
| PUBMED: | 22773832 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 1 October 2012" - "CODEN: JBCHA" - "Source: Scopus" |
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