1. Human Biology and Medicine
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KRAS-dependent sorting of miRNA to exosomes

  1. Diana J Cha
  2. Jeffrey L Franklin
  3. Yongchao Dou
  4. Qi Liu
  5. James N Higginbotham
  6. Michelle Demory Beckler
  7. Alissa M Weaver
  8. Kasey Vickers
  9. Nirpesh Prasad
  10. Shawn Levy
  11. Bing Zhang
  12. Robert J Coffey
  13. James G Patton  Is a corresponding author
  1. Vanderbilt University Medical Center, United States
  2. HudsonAlpha Institute for Biotechnology, United States
Research Article
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Cite this article as: eLife 2015;4:e07197 doi: 10.7554/eLife.07197

Abstract

Mutant KRAS colorectal cancer (CRC) cells release protein-laden exosomes that can alter the tumor microenvironment. To test whether exosomal RNAs also contribute to changes in gene expression in recipient cells, and whether mutant KRAS might regulate the composition of secreted miRNAs, we compared small RNAs of cells and matched exosomes from isogenic CRC cell lines differing only in KRAS status. We show that exosomal profiles are distinct from cellular profiles, and mutant exosomes cluster separately from wild type KRAS exosomes. miR-10b was selectively increased in wild type exosomes while miR-100 was increased in mutant exosomes. Neutral sphingomyelinase inhibition caused accumulation of miR-100 only in mutant cells, suggesting KRAS-dependent miRNA export. In Transwell co-culture experiments, mutant donor cells conferred miR-100-mediated target repression in wild type recipient cells. These findings suggest extracellular miRNAs can function in target cells and uncover a potential new mode of action for mutant KRAS in CRC.

Article and author information

Author details

  1. Diana J Cha

    Department of Biological Sciences, Vanderbilt University Medical Center, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Jeffrey L Franklin

    Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Yongchao Dou

    Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Qi Liu

    Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. James N Higginbotham

    Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Michelle Demory Beckler

    Department of Medicine, Vanderbilt University Medical Center, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Alissa M Weaver

    Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Kasey Vickers

    Department of Cardiology, Vanderbilt University Medical Center, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Nirpesh Prasad

    HudsonAlpha Institute for Biotechnology, Huntsville, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Shawn Levy

    HudsonAlpha Institute for Biotechnology, Huntsville, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Bing Zhang

    Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Robert J Coffey

    Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. James G Patton

    Department of Biological Sciences, Vanderbilt University Medical Center, Nashville, United States
    For correspondence
    james.g.patton@vanderbilt.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Phillip D Zamore, Howard Hughes Medical Institute, University of Massachusetts Medical School, United States

Publication history

  1. Received: February 26, 2015
  2. Accepted: June 29, 2015
  3. Accepted Manuscript published: July 1, 2015 (version 1)
  4. Version of Record published: July 22, 2015 (version 2)

Copyright

© 2015, Cha et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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