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

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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 Hras^G12V on the transcriptome of keratinocytes. We discover that microRNA-203 is downregulated by Hras^G12V. 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.

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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.
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.
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.
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.
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.

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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.