title: Upregulation of miR-203 and miR-210 affect growth and differentiation of keratinocytes after exposure to sulfur mustard in normoxia and hypoxia.
abstract: Exposure of the skin to sulfur mustard (SM) results in long-term complications such as impaired tissue regeneration. Previous own studies in normal human epidermal keratinocytes (NHEK) treated with SM demonstrated reduced proliferation, premature differentiation and a restricted functionality of hypoxia-mediated signaling in the cells. Here, we investigated the involvement of microRNAs, miR-203 and miR-210, in these mechanisms. SM significantly upregulated the expression of miR-203 in NHEK when cultivated under normoxic and hypoxic conditions. SM had no effect on miR-210 under normoxia. However, miR-210 levels were greatly increased in NHEK when grown in hypoxia and further elevated upon exposure of the cells to SM. In normoxia and hypoxia, inhibition of miR-203 by transfection of NHEK with complementary oligonucleotides, anti-miR-203, attenuated the SM-induced impairment of metabolic activity and proliferation, and counteracted SM-promoted keratin-1 expression in these cells. Consistent ameliorating effects on dysregulated metabolic activity, proliferation and keratin-1 expression in SM-treated NHEK were obtained upon inhibition of miR-210 in these cells grown in hypoxia. Our findings provide evidence that miR-203 and miR-210 are key regulators in normal and SM-impaired keratinocyte functionality, and suggest potential usefulness of inhibitors against miR-203 and miR-210 for target-directed therapeutical intervention to improve re-epithelialization of SM-injured skin.
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Janina
authors.initials: J
authors.lastname: Deppe
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany; Walther-Straub-Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Steinritz
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany; European Center of Excellence on Atherosclerosis, Hypertension and Dyslipidemia, G. d'Annunzio University, 66100 Chieti, Italy.
authors.forename: Donato
authors.initials: D
authors.lastname: Santovito
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Virginia
authors.initials: V
authors.lastname: Egea
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Schmidt
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany. Electronic address: christian.ries@med.uni-muenchen.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Ries
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects*; D015687:Cell Hypoxia; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D002619:Chemical Warfare Agents / Q000633:toxicity*; D006801:Humans; D053556:Keratin-1 / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009151:Mustard Gas / Q000633:toxicity*; D009841:Oligonucleotides / Q000235:genetics / Q000378:metabolism; D062326:Re-Epithelialization; D014162:Transfection; D015854:Up-Regulation
chemical_list: D002619:Chemical Warfare Agents; C491616:KRT1 protein, human; D053556:Keratin-1; C546703:MIRN203 microRNA, human; C543800:MIRN210 microRNA, human; D035683:MicroRNAs; D009841:Oligonucleotides; D009151:Mustard Gas
keywords: Hypoxia; Keratinocyte proliferation and differentiation; MicroRNA; Sulfur mustard; Wound healing