title: The proto-oncogene TWIST1 is regulated by microRNAs.
abstract: Upregulation of the proto-oncogene Twist1 is highly correlated with acquired drug resistance and poor prognosis in human cancers. Altered expression of this multifunctional transcription factor is also associated with inherited skeletal malformations. The mammalian Twist1 3'UTRs are highly conserved and contain a number of potential regulatory elements including miRNA target sites. We analyzed the translational regulation of TWIST1 using luciferase reporter assays in a variety of cell lines. Among several miRNAs tested, miR-145a-5p, miR-151-5p and a combination of miR-145a-5p + miR-151-5p and miR-151-5p + miR-337-3p were able to significantly repress Twist1 translation. This phenomena was confirmed with both exogenous and endogenous miRNAs and was dependent on the presence of the predicted target sites in the 3'UTR. Furthermore, the repression was sensitive to LNA-modified miRNA antagonists and resulted in decreased migratory potential of murine embryonic fibroblast cells. Understanding the in vivo mechanisms of this oncogene's regulation might open up a possibility for therapeutic interference by gene specific cancer therapies.
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
authors.forename: Maarja-Liisa
authors.initials: ML
authors.lastname: Nairismägi
authors.forename: Annette
authors.initials: A
authors.lastname: Füchtbauer
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Labouriau
authors.forename: Jesper Bertram
authors.initials: JB
authors.lastname: Bramsen
authors.forename: Ernst-Martin
authors.initials: EM
authors.lastname: Füchtbauer
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D002417:Cattle; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics; D002645:Chickens; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics*; D014176:Protein Biosynthesis / Q000235:genetics; D000090063:Proto-Oncogene Mas; D011519:Proto-Oncogenes; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics; D016415:Sequence Alignment; D051879:Twist-Related Protein 1 / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; C000715470:MAS1 protein, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D000090063:Proto-Oncogene Mas; D012097:Repressor Proteins; C103173:TWIST1 protein, human; C486274:TWIST2 protein, human; D051879:Twist-Related Protein 1