1. Developmental Biology
  2. Cancer Biology
Download icon

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
Research Article
  • Cited 11
  • Views 1,586
  • Annotations
Cite this article as: eLife 2015;4:e07004 doi: 10.7554/eLife.07004

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.

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.

Reviewing Editor

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

Publication 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

  • 1,586
    Page views
  • 305
    Downloads
  • 11
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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)

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

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

Further reading

    1. Developmental Biology
    Christian SM Helker et al.
    Research Article

    To form new blood vessels (angiogenesis), endothelial cells (ECs) must be activated and acquire highly migratory and proliferative phenotypes. However, the molecular mechanisms that govern these processes are incompletely understood. Here, we show that Apelin signaling functions to drive ECs into such an angiogenic state. Zebrafish lacking Apelin signaling exhibit defects in endothelial tip cell morphology and sprouting. Using transplantation experiments, we find that in mosaic vessels, wild-type ECs leave the dorsal aorta (DA) and form new vessels while neighboring ECs defective in Apelin signaling remain in the DA. Mechanistically, Apelin signaling enhances glycolytic activity in ECs at least in part by increasing levels of the growth-promoting transcription factor c-Myc. Moreover, Apelin expression is regulated by Notch signaling, and its function is required for the hypersprouting phenotype in Delta-like 4 (Dll4) knockdown embryos. These data provide new insights into fundamental principles of blood vessel formation and Apelin signaling, enabling a better understanding of vascular growth in health and disease.

    1. Developmental Biology
    Néstor Saiz et al.
    Research Article Updated

    Precise control and maintenance of population size is fundamental for organismal development and homeostasis. The three cell types of the mammalian blastocyst are generated in precise proportions over a short time, suggesting a mechanism to ensure a reproducible outcome. We developed a minimal mathematical model demonstrating growth factor signaling is sufficient to guarantee this robustness and which anticipates an embryo's response to perturbations in lineage composition. Addition of lineage-restricted cells both in vivo and in silico, causes a shift of the fate of progenitors away from the supernumerary cell type, while eliminating cells using laser ablation biases the specification of progenitors toward the targeted cell type. Finally, FGF4 couples fate decisions to lineage composition through changes in local growth factor concentration, providing a basis for the regulative abilities of the early mammalian embryo whereby fate decisions are coordinated at the population level to robustly generate tissues in the right proportions.