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Cancer Res. 2014 Oct 15;74(20):5758-71. doi: 10.1158/0008-5472.CAN-13-3512. Epub 2014 Sep 26.

Cellular disposal of miR23b by RAB27-dependent exosome release is linked to acquisition of metastatic properties.

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Department of Molecular Medicine (MOMA), Aarhus University Hospital, Skejby, Denmark.
Department of Molecular Medicine (MOMA), Aarhus University Hospital, Skejby, Denmark.
The interdisciplinary Nanoscience Center (iNANO), Aarhus University, Denmark.
Laboratory of Experimental Cancer Research, Ghent University Hospital, Belgium.
Department of Biomedicine, Aarhus University, Denmark.
EMBL Heidelberg, Heidelberg, Germany.
Department of Biomedicine-Anatomy, University of Aarhus, Denmark.
Centre for Molecular Medicine Norway (NCMM), University of Oslo, Norway.
Department of Urology, Aarhus University Hospital, Denmark.
University of Colorado Cancer Center, Aurora, Colorado, USA.


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.

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