title: Versican 3'-untranslated region (3'UTR) promotes dermal wound repair and fibroblast migration by regulating miRNA activity.
abstract: Versican is an extracellular chondroitin sulfate proteoglycan which functions as a structural molecule but can also regulate a variety of cellular activities. This study was designed to explore the roles of versican in the process of dermal wound repair. To elevate levels of versican, we ectopically expressed the versican 3'-untranslated region (3'UTR) as a competitive endogenous RNA to modulate expression of versican. We demonstrated that wounds closed faster in transgenic mice expressing the versican 3'UTR, as compared to those in wildtype mice. We stably expressed versican 3'UTR in NIH3T3 fibroblasts and found that the 3'UTR-transfected cells showed increased migratory capacity relative to vector-transfected cells. Interestingly, we found that the 3'UTRs of versican and β-catenin shared common microRNAs (miRNAs) including miR-185, miR-203*, miR-690, miR-680, and miR-434-3p. Luciferase assays showed that all of these miRNAs could target the 3'UTRs of both versican and β-catenin, when the luciferase constructs contained fragments harboring the miRNA binding sites. As a consequence, expression of both versican and β-catenin was up-regulated, which was confirmed in vitro and in vivo. Transfection with small interfering RNAs (siRNAs) targeting the versican 3'UTR abolished the 3'UTR's effects on cell migration and invasion. Taken together, these results demonstrate that versican plays important roles in wound repair and that versican messenger RNAs (mRNAs) could compete with endogenous RNAs for regulating miRNA functions.
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre and Centre for the Study of Bone Metastasis, Odette Cancer Centre, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Weining
authors.initials: W
authors.lastname: Yang
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre and Centre for the Study of Bone Metastasis, Odette Cancer Centre, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. Electronic address: albert.yee@sunnybrook.ca.
authors.forename: Albert J M
authors.initials: AJ
authors.lastname: Yee
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D002465:Cell Movement / Q000235:genetics; D020405:Dermis / Q000293:injuries / Q000378:metabolism*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D053675:Versicans / Q000235:genetics / Q000378:metabolism*; D014945:Wound Healing / Q000235:genetics*; D051176:beta Catenin
chemical_list: D020413:3' Untranslated Regions; C495267:CTNNB1 protein, mouse; D035683:MicroRNAs; D034741:RNA, Small Interfering; D051176:beta Catenin; D053675:Versicans; D008156:Luciferases
keywords: 3′UTR; CeRNA; MicroRNA; Non-coding RNA; Transgenic mouse