Induction of Specific MicroRNAs Inhibits Cutaneous Wound Healing

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 biopsie...

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Veröffentlicht in:The Journal of biological chemistry 2012-08, Vol.287 (35), p.29324-29335
Hauptverfasser: Pastar, Irena, Khan, Aly Azeem, Stojadinovic, Olivera, Lebrun, Elizabeth A., Medina, Mayrin Correa, Brem, Harold, Kirsner, Robert S., Jimenez, Joaquin J., Leslie, Christina, Tomic-Canic, Marjana
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container_end_page 29335
container_issue 35
container_start_page 29324
container_title The Journal of biological chemistry
container_volume 287
creator Pastar, Irena
Khan, Aly Azeem
Stojadinovic, Olivera
Lebrun, Elizabeth A.
Medina, Mayrin Correa
Brem, Harold
Kirsner, Robert S.
Jimenez, Joaquin J.
Leslie, Christina
Tomic-Canic, Marjana
description 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. Background: Venous ulcers (VUs) are a major health problem, but their molecular pathology remains unknown. Results: A specific set of miRNAs induced in VUs targets signaling molecules and inhibits healing. Conclusion: Induction of miRNAs in VUs leads to inhibition of epithelialization and granulation tissue formation. Significance: This new discovery will enable miRNA use as diagnostic/therapeutic targets in VUs.
doi_str_mv 10.1074/jbc.M112.382135
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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. Background: Venous ulcers (VUs) are a major health problem, but their molecular pathology remains unknown. Results: A specific set of miRNAs induced in VUs targets signaling molecules and inhibits healing. Conclusion: Induction of miRNAs in VUs leads to inhibition of epithelialization and granulation tissue formation. 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Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><rights>2012 by The American Society for Biochemistry and Molecular Biology, Inc. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c509t-dfff9321da8860fa066a851f6962b10cf25e2597b26f9d3b70922b52437b28013</citedby><cites>FETCH-LOGICAL-c509t-dfff9321da8860fa066a851f6962b10cf25e2597b26f9d3b70922b52437b28013</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3436197/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3436197/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22773832$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pastar, Irena</creatorcontrib><creatorcontrib>Khan, Aly Azeem</creatorcontrib><creatorcontrib>Stojadinovic, Olivera</creatorcontrib><creatorcontrib>Lebrun, Elizabeth A.</creatorcontrib><creatorcontrib>Medina, Mayrin Correa</creatorcontrib><creatorcontrib>Brem, Harold</creatorcontrib><creatorcontrib>Kirsner, Robert S.</creatorcontrib><creatorcontrib>Jimenez, Joaquin J.</creatorcontrib><creatorcontrib>Leslie, Christina</creatorcontrib><creatorcontrib>Tomic-Canic, Marjana</creatorcontrib><title>Induction of Specific MicroRNAs Inhibits Cutaneous Wound Healing</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Chronic nonhealing wounds, such as venous ulcers (VUs), are a widespread and serious medical problem with high morbidity and mortality. 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Khan, Aly Azeem ; Stojadinovic, Olivera ; Lebrun, Elizabeth A. ; Medina, Mayrin Correa ; Brem, Harold ; Kirsner, Robert S. ; Jimenez, Joaquin J. ; Leslie, Christina ; Tomic-Canic, Marjana</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c509t-dfff9321da8860fa066a851f6962b10cf25e2597b26f9d3b70922b52437b28013</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Animals</topic><topic>Chickens</topic><topic>Chronic Wounds</topic><topic>Disease Models, Animal</topic><topic>Dogs</topic><topic>Early Growth Response Protein 1 - genetics</topic><topic>Early Growth Response Protein 1 - metabolism</topic><topic>Epidermis</topic><topic>Epithelialization</topic><topic>Female</topic><topic>Gene Expression Regulation</topic><topic>Granulation Tissue</topic><topic>Humans</topic><topic>Keratinocytes</topic><topic>Male</topic><topic>Mice</topic><topic>Microarray</topic><topic>MicroRNA</topic><topic>MicroRNAs - biosynthesis</topic><topic>MicroRNAs - genetics</topic><topic>Middle Aged</topic><topic>Molecular Bases of Disease</topic><topic>Rats</topic><topic>Rats, Long-Evans</topic><topic>Receptors, Leptin - genetics</topic><topic>Receptors, Leptin - metabolism</topic><topic>Skin</topic><topic>Skin - injuries</topic><topic>Skin - metabolism</topic><topic>Skin - pathology</topic><topic>Transcriptome</topic><topic>Venous Ulcers</topic><topic>Wound Healing</topic><topic>Wound Healing - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pastar, Irena</creatorcontrib><creatorcontrib>Khan, Aly Azeem</creatorcontrib><creatorcontrib>Stojadinovic, Olivera</creatorcontrib><creatorcontrib>Lebrun, Elizabeth A.</creatorcontrib><creatorcontrib>Medina, Mayrin Correa</creatorcontrib><creatorcontrib>Brem, Harold</creatorcontrib><creatorcontrib>Kirsner, Robert S.</creatorcontrib><creatorcontrib>Jimenez, Joaquin J.</creatorcontrib><creatorcontrib>Leslie, Christina</creatorcontrib><creatorcontrib>Tomic-Canic, Marjana</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pastar, Irena</au><au>Khan, Aly Azeem</au><au>Stojadinovic, Olivera</au><au>Lebrun, Elizabeth A.</au><au>Medina, Mayrin Correa</au><au>Brem, Harold</au><au>Kirsner, Robert S.</au><au>Jimenez, Joaquin J.</au><au>Leslie, Christina</au><au>Tomic-Canic, Marjana</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Induction of Specific MicroRNAs Inhibits Cutaneous Wound Healing</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2012-08-24</date><risdate>2012</risdate><volume>287</volume><issue>35</issue><spage>29324</spage><epage>29335</epage><pages>29324-29335</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><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. Background: Venous ulcers (VUs) are a major health problem, but their molecular pathology remains unknown. Results: A specific set of miRNAs induced in VUs targets signaling molecules and inhibits healing. Conclusion: Induction of miRNAs in VUs leads to inhibition of epithelialization and granulation tissue formation. Significance: This new discovery will enable miRNA use as diagnostic/therapeutic targets in VUs.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>22773832</pmid><doi>10.1074/jbc.M112.382135</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record>
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subjects Adult
Aged
Aged, 80 and over
Animals
Chickens
Chronic Wounds
Disease Models, Animal
Dogs
Early Growth Response Protein 1 - genetics
Early Growth Response Protein 1 - metabolism
Epidermis
Epithelialization
Female
Gene Expression Regulation
Granulation Tissue
Humans
Keratinocytes
Male
Mice
Microarray
MicroRNA
MicroRNAs - biosynthesis
MicroRNAs - genetics
Middle Aged
Molecular Bases of Disease
Rats
Rats, Long-Evans
Receptors, Leptin - genetics
Receptors, Leptin - metabolism
Skin
Skin - injuries
Skin - metabolism
Skin - pathology
Transcriptome
Venous Ulcers
Wound Healing
Wound Healing - physiology
title Induction of Specific MicroRNAs Inhibits Cutaneous Wound Healing
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