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.

Metrics

  • 1,780
    views
  • 317
    downloads
  • 16
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Further reading

    1. Developmental Biology
    Amandine Jarysta, Abigail LD Tadenev ... Basile Tarchini
    Research Article

    Inhibitory G alpha (GNAI or Gαi) proteins are critical for the polarized morphogenesis of sensory hair cells and for hearing. The extent and nature of their actual contributions remains unclear, however, as previous studies did not investigate all GNAI proteins and included non-physiological approaches. Pertussis toxin can downregulate functionally redundant GNAI1, GNAI2, GNAI3, and GNAO proteins, but may also induce unrelated defects. Here, we directly and systematically determine the role(s) of each individual GNAI protein in mouse auditory hair cells. GNAI2 and GNAI3 are similarly polarized at the hair cell apex with their binding partner G protein signaling modulator 2 (GPSM2), whereas GNAI1 and GNAO are not detected. In Gnai3 mutants, GNAI2 progressively fails to fully occupy the sub-cellular compartments where GNAI3 is missing. In contrast, GNAI3 can fully compensate for the loss of GNAI2 and is essential for hair bundle morphogenesis and auditory function. Simultaneous inactivation of Gnai2 and Gnai3 recapitulates for the first time two distinct types of defects only observed so far with pertussis toxin: (1) a delay or failure of the basal body to migrate off-center in prospective hair cells, and (2) a reversal in the orientation of some hair cell types. We conclude that GNAI proteins are critical for hair cells to break planar symmetry and to orient properly before GNAI2/3 regulate hair bundle morphogenesis with GPSM2.

    1. Computational and Systems Biology
    2. Developmental Biology
    Gang Xue, Xiaoyi Zhang ... Zhiyuan Li
    Research Article

    Organisms utilize gene regulatory networks (GRN) to make fate decisions, but the regulatory mechanisms of transcription factors (TF) in GRNs are exceedingly intricate. A longstanding question in this field is how these tangled interactions synergistically contribute to decision-making procedures. To comprehensively understand the role of regulatory logic in cell fate decisions, we constructed a logic-incorporated GRN model and examined its behavior under two distinct driving forces (noise-driven and signal-driven). Under the noise-driven mode, we distilled the relationship among fate bias, regulatory logic, and noise profile. Under the signal-driven mode, we bridged regulatory logic and progression-accuracy trade-off, and uncovered distinctive trajectories of reprogramming influenced by logic motifs. In differentiation, we characterized a special logic-dependent priming stage by the solution landscape. Finally, we applied our findings to decipher three biological instances: hematopoiesis, embryogenesis, and trans-differentiation. Orthogonal to the classical analysis of expression profile, we harnessed noise patterns to construct the GRN corresponding to fate transition. Our work presents a generalizable framework for top-down fate-decision studies and a practical approach to the taxonomy of cell fate decisions.