title: Cellular disposal of miR23b by RAB27-dependent exosome release is linked to acquisition of metastatic properties.
abstract: Exosomes are small secreted vesicles that can transfer their content to recipient cells. In cancer, exosome secretion has been implicated in tumor growth and metastatic spread. In this study, we explored the possibility that exosomal pathways might discard tumor-suppressor miRNA that restricts metastatic progression. Secreted miRNA characterized from isogenic bladder carcinoma cell lines with differing metastatic potential were uncoupled from binding to target transcripts or the AGO2-miRISC complex. In metastatic cells, we observed a relative increase in secretion of miRNA with tumor-suppressor functions, including miR23b, miR224, and miR921. Ectopic expression of miR23b inhibited invasion, anoikis, angiogenesis, and pulmonary metastasis. Silencing of the exocytotic RAB family members RAB27A or RAB27B halted miR23b and miR921 secretion and reduced cellular invasion. Clinically, elevated levels of RAB27B expression were linked to poor prognosis in two independent cohorts of patients with bladder cancer. Moreover, highly exocytosed miRNA from metastatic cells, such as miR23b, were reduced in lymph node metastases compared with patient-matched primary tumors and were correlated with increments in miRNA-targeted RNA. Taken together, our results suggested that exosome-mediated secretion of tumor-suppressor miRNA is selected during tumor progression as a mechanism to coordinate activation of a metastatic cascade.
authors.affiliation: Department of Molecular Medicine (MOMA), Aarhus University Hospital, Skejby, Denmark. marie.stampe@clin.au.dk orntoft@clin.au.dk.
authors.forename: Marie Stampe
authors.initials: MS
authors.lastname: Ostenfeld
authors.affiliation: Department of Molecular Medicine (MOMA), Aarhus University Hospital, Skejby, Denmark.
authors.forename: Dennis K
authors.initials: DK
authors.lastname: Jeppesen
authors.affiliation: Department of Molecular Medicine (MOMA), Aarhus University Hospital, Skejby, Denmark.
authors.forename: Jens R
authors.initials: JR
authors.lastname: Laurberg
authors.affiliation: The interdisciplinary Nanoscience Center (iNANO), Aarhus University, Denmark.
authors.forename: Anders T
authors.initials: AT
authors.lastname: Boysen
authors.affiliation: Department of Molecular Medicine (MOMA), Aarhus University Hospital, Skejby, Denmark.
authors.forename: Jesper B
authors.initials: JB
authors.lastname: Bramsen
authors.affiliation: Department of Molecular Medicine (MOMA), Aarhus University Hospital, Skejby, Denmark.
authors.forename: Bjarke
authors.initials: B
authors.lastname: Primdal-Bengtson
authors.affiliation: Laboratory of Experimental Cancer Research, Ghent University Hospital, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Hendrix
authors.affiliation: Department of Molecular Medicine (MOMA), Aarhus University Hospital, Skejby, Denmark.
authors.forename: Philippe
authors.initials: P
authors.lastname: Lamy
authors.affiliation: Department of Biomedicine, Aarhus University, Denmark.
authors.forename: Frederik
authors.initials: F
authors.lastname: Dagnaes-Hansen
authors.affiliation: Department of Molecular Medicine (MOMA), Aarhus University Hospital, Skejby, Denmark.
authors.forename: Mads H
authors.initials: MH
authors.lastname: Rasmussen
authors.affiliation: EMBL Heidelberg, Heidelberg, Germany.
authors.forename: Khan H
authors.initials: KH
authors.lastname: Bui
authors.affiliation: Department of Molecular Medicine (MOMA), Aarhus University Hospital, Skejby, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Fristrup
authors.affiliation: Department of Biomedicine-Anatomy, University of Aarhus, Denmark.
authors.forename: Erik I
authors.initials: EI
authors.lastname: Christensen
authors.affiliation: Department of Molecular Medicine (MOMA), Aarhus University Hospital, Skejby, Denmark.
authors.forename: Iver
authors.initials: I
authors.lastname: Nordentoft
authors.affiliation: Centre for Molecular Medicine Norway (NCMM), University of Oslo, Norway.
authors.forename: Jens P
authors.initials: JP
authors.lastname: Morth
authors.affiliation: Department of Urology, Aarhus University Hospital, Denmark.
authors.forename: Jørgen B
authors.initials: JB
authors.lastname: Jensen
authors.affiliation: Department of Molecular Medicine (MOMA), Aarhus University Hospital, Skejby, Denmark.
authors.forename: Jakob S
authors.initials: JS
authors.lastname: Pedersen
authors.affiliation: EMBL Heidelberg, Heidelberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Beck
authors.affiliation: University of Colorado Cancer Center, Aurora, Colorado, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Theodorescu
authors.affiliation: Department of Urology, Aarhus University Hospital, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Borre
authors.affiliation: The interdisciplinary Nanoscience Center (iNANO), Aarhus University, Denmark.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Howard
authors.affiliation: Department of Molecular Medicine (MOMA), Aarhus University Hospital, Skejby, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Dyrskjøt
authors.affiliation: Department of Molecular Medicine (MOMA), Aarhus University Hospital, Skejby, Denmark. marie.stampe@clin.au.dk orntoft@clin.au.dk.
authors.forename: Torben Falck
authors.initials: TF
authors.lastname: Ørntoft
mesh_terms: D000818:Animals; D002295:Carcinoma, Transitional Cell / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D045744:Cell Line, Tumor; D005089:Exocytosis; D055354:Exosomes / Q000378:metabolism*; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D034622:RNA Interference; D059467:Transcriptome; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D020691:rab GTP-Binding Proteins / Q000502:physiology*; D000075745:rab27 GTP-Binding Proteins
chemical_list: C552430:MIRN23a microRNA, human; C580863:MIRN921, human; D035683:MicroRNAs; D000075745:rab27 GTP-Binding Proteins; C066694:RAB27A protein, human; C512960:Rab27B protein, human; D020691:rab GTP-Binding Proteins