Cellular Disposal of miR23b by RAB27-Dependent Exosome Release Is Linked to Acquisition of Metastatic Properties

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  • Marie Stampe Ostenfeld, Department of Molecular Medicine (MOMA), Aarhus University Hospital, Skejby, Denmark., Denmark
  • Dennis K Jeppesen, Department of Molecular Medicine (MOMA), Aarhus University Hospital, Skejby, Denmark., Denmark
  • Jens R Laurberg, Department of Molecular Medicine (MOMA), Aarhus University Hospital, Skejby, Denmark., Denmark
  • Anders T Boysen
  • Jesper B Bramsen
  • Bjarke Primdal-Bengtson, Department of Molecular Medicine (MOMA), Aarhus University Hospital, Skejby, Denmark., Denmark
  • An Hendrix, Laboratory of Experimental Cancer Research, Ghent University Hospital, Belgium., Unknown
  • Philippe Lamy
  • Frederik Dagnaes-Hansen, Department of Biomedicine, Aarhus University, Denmark., Denmark
  • Mads H Rasmussen
  • Khan H Bui, EMBL Heidelberg, Heidelberg, Germany
  • ,
  • Niels Fristrup
  • Erik I Christensen
  • Iver Nordentoft
  • Jens P Morth, Centre for Molecular Medicine Norway (NCMM), University of Oslo, Norway, Denmark
  • Jørgen B Jensen
  • Jakob S Pedersen
  • Martin Beck, EMBL Heidelberg, Heidelberg, Germany, Unknown
  • Dan Theodorescu, University of Colorado Cancer Center, Aurora, Colorado, USA.
  • ,
  • Michael Borre
  • Kenneth Alan Howard, The interdisciplinary Nanoscience Center (iNANO), Aarhus University, Denmark., LUKKET: 2012 Institut for Farmaci, Denmark
  • Lars Dyrskjøt
  • Torben Falck Orntoft

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. Cancer Res; 74(20); 1-14. ©2014 AACR.

Original languageEnglish
JournalCancer Research
Volume74
Issue20
Pages (from-to)5758-5771
ISSN0008-5472
DOIs
Publication statusPublished - 26 Sep 2014

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