title: Rapid decay of engulfed extracellular miRNA by XRN1 exonuclease promotes transient epithelial-mesenchymal transition.
abstract: Extracellular vesicles (EVs) have been shown to play an important role in intercellular communication as carriers of DNA, RNA and proteins. While the intercellular transfer of miRNA through EVs has been extensively studied, the stability of extracellular miRNA (ex-miRNA) once engulfed by a recipient cell remains to be determined. Here, we identify the ex-miRNA-directed phenotype to be transient due to the rapid decay of ex-miRNA. We demonstrate that the ex-miR-223-3p transferred from polymorphonuclear leukocytes to cancer cells were functional, as demonstrated by the decreased expression of its target FOXO1 and the occurrence of epithelial-mesenchymal transition reprogramming. We showed that the engulfed ex-miRNA, unlike endogenous miRNA, was unstable, enabling dynamic regulation and a return to a non-invasive phenotype within 8 h. This transient phenotype could be modulated by targeting XRN1/PACMAN exonuclease. Indeed, its silencing was associated with slower decay of ex-miR-223-3p and subsequently prolonged the invasive properties. In conclusion, we showed that the 'steady step' level of engulfed miRNA and its subsequent activity was dependent on the presence of a donor cell in the surroundings to constantly fuel the recipient cell with ex-miRNAs and of XRN1 exonuclease, which is involved in the decay of these imported miRNA.
authors.affiliation: Université Côte d'Azur, CNRS, INSERM, IRCAN, FHU-OncoAge, 06107 Nice France.
authors.forename: Joséphine
authors.initials: J
authors.lastname: Zangari
authors.affiliation: Université Côte d'Azur, CNRS, INSERM, IRCAN, FHU-OncoAge, 06107 Nice France.|Université Côte d'Azur, CHU-Nice, Hospital-related Biobank (BB-0033-00025), FHU-OncoAge, 06000 Nice, France.
authors.forename: Marius
authors.initials: M
authors.lastname: Ilie
authors.affiliation: Université Côte d'Azur, INSERM, C3M, 06200 Nice, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Rouaud
authors.affiliation: Université Côte d'Azur, CNRS, INSERM, IRCAN, FHU-OncoAge, 06107 Nice France.
authors.forename: Laurie
authors.initials: L
authors.lastname: Signetti
authors.affiliation: Université Côte d'Azur, INSERM, C3M, 06200 Nice, France.
authors.forename: Mickaël
authors.initials: M
authors.lastname: Ohanna
authors.affiliation: Université Côte d'Azur, INSERM, C3M, 06200 Nice, France.
authors.forename: Robin
authors.initials: R
authors.lastname: Didier
authors.affiliation: Université Côte d'Azur, CNRS, INSERM, IRCAN, FHU-OncoAge, 06107 Nice France.
authors.forename: Barnabé
authors.initials: B
authors.lastname: Roméo
authors.affiliation: Université Côte d'Azur, CNRS, INSERM, IRCAN, FHU-OncoAge, 06107 Nice France.
authors.forename: Dana
authors.initials: D
authors.lastname: Goldoni
authors.affiliation: Université Côte d'Azur, CNRS, INSERM, IPMC, FHU-OncoAge, 06560 Valbonne, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Nottet
authors.affiliation: Université de Bordeaux, INSERM, ARNA, 33076 Bordeaux, France.
authors.forename: Cathy
authors.initials: C
authors.lastname: Staedel
authors.affiliation: Antoine Lacassagne Cancer Center, Epidemiology and Biostatistics Unit, 06189 Nice, France.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Gal
authors.affiliation: Université Côte d'Azur, CNRS, INSERM, IPMC, FHU-OncoAge, 06560 Valbonne, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Mari
authors.affiliation: Université Côte d'Azur, CNRS, INSERM, IRCAN, FHU-OncoAge, 06107 Nice France.
authors.forename: Baharia
authors.initials: B
authors.lastname: Mograbi
authors.affiliation: Université Côte d'Azur, CNRS, INSERM, IRCAN, FHU-OncoAge, 06107 Nice France.|Université Côte d'Azur, CHU-Nice, Hospital-related Biobank (BB-0033-00025), FHU-OncoAge, 06000 Nice, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Hofman
authors.affiliation: Université Côte d'Azur, CNRS, INSERM, IRCAN, FHU-OncoAge, 06107 Nice France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Brest
mesh_terms: D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005095:Exoribonucleases / Q000378:metabolism*; D055354:Exosomes / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009504:Neutrophils / Q000378:metabolism; D020871:RNA Stability
chemical_list: D005095:Exoribonucleases; D035683:MicroRNAs; D008869:Microtubule-Associated Proteins; C525067:MIR223, human; C470512:XRN1 protein, human