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.
authors: Wound Healing and Regenerative Medicine Research Program, Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors: Irena
authors: I
authors: Pastar
authors: Aly Azeem
authors: AA
authors: Khan
authors: Olivera
authors: O
authors: Stojadinovic
authors: Elizabeth A
authors: EA
authors: Lebrun
authors: Mayrin Correa
authors: MC
authors: Medina
authors: Harold
authors: H
authors: Brem
authors: Robert S
authors: RS
authors: Kirsner
authors: Joaquin J
authors: JJ
authors: Jimenez
authors: Christina
authors: C
authors: Leslie
authors: Marjana
authors: M
authors: Tomic-Canic
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002645:Chickens; D004195:Disease Models, Animal; D004285:Dogs; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D051381:Rats; D020318:Rats, Long-Evans; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000293:injuries* / Q000378:metabolism* / Q000473:pathology; D059467:Transcriptome; D014945:Wound Healing / Q000502:physiology*
chemical_list: C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; C486110:Egr1 protein, rat; C515448:LEPR protein, human; D035683:MicroRNAs; D054411:Receptors, Leptin; C515447:leptin receptor, mouse