MicroRNA-203 represses selection and expansion of oncogenic Hras transformed tumor initiating cells

  1. Kent Riemondy
  2. Xiao-jing Wang
  3. Enrique C Torchia
  4. Dennis R Roop
  5. Rui Yi  Is a corresponding author
  1. University of Colorado, Boulder, United States
  2. University of Colorado Denver Anschutz Medical Campus, United States

Abstract

In many mouse models of skin cancer, only a few tumors typically form even though many cells competent for tumorigenesis receive the same oncogenic stimuli. These observations suggest an active selection process for tumor-initiating cells. Here we use quantitative mRNA- and miR-Seq to determine the impact of HrasG12V on the transcriptome of keratinocytes. We discover that microRNA-203 is downregulated by HrasG12V. Using a knockout mouse model, we demonstrate that loss of microRNA-203 promotes selection and expansion of tumor-initiating cells. Conversely, restoration of microRNA-203 using an inducible model potently inhibits proliferation of these cells. We comprehensively identify microRNA-203 targets required for Hras-initiated tumorigenesis. These targets include critical regulators of the Ras pathway and essential genes required for cell division. This study establishes a role for the loss of microRNA-203 in promoting selection and expansion of Hras mutated cells and identifies a mechanism through which microRNA-203 antagonizes Hras-mediated tumorigenesis.

Article and author information

Author details

  1. Kent Riemondy

    Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Boulder, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Xiao-jing Wang

    Department of Pathology, University of Colorado Denver Anschutz Medical Campus, Denver, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Enrique C Torchia

    Department of Dermatology, University of Colorado Denver Anschutz Medical Campus, Denver, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Dennis R Roop

    Department of Dermatology, University of Colorado Denver Anschutz Medical Campus, Denver, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Rui Yi

    Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Boulder, United States
    For correspondence
    yir@colorado.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Chi Van Dang, University of Pennsylvania, United States

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#1408.01) of the University of Colorado, Boulder. Every effort was made to minimize suffering.

Version history

  1. Received: February 13, 2015
  2. Accepted: July 22, 2015
  3. Accepted Manuscript published: July 23, 2015 (version 1)
  4. Version of Record published: August 14, 2015 (version 2)

Copyright

© 2015, Riemondy 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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  1. Kent Riemondy
  2. Xiao-jing Wang
  3. Enrique C Torchia
  4. Dennis R Roop
  5. Rui Yi
(2015)
MicroRNA-203 represses selection and expansion of oncogenic Hras transformed tumor initiating cells
eLife 4:e07004.
https://doi.org/10.7554/eLife.07004

Share this article

https://doi.org/10.7554/eLife.07004

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