Concomitant suppression of three target genes can explain the impact of a microRNA on metastasis
- Scott Valastyan1,2,
- Nathan Benaich1,3,
- Amelia Chang1,2,
- Ferenc Reinhardt1 and
- Robert A. Weinberg1,2,4,5
- 1Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA;
- 2Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
- 3Department of Biology, Williams College, Williamstown, Massachusetts 01267, USA;
- 4Massachusetts Institute of Technology Ludwig Center for Molecular Oncology, Cambridge, Massachusetts 02139, USA
Abstract
It remains unclear whether a microRNA (miRNA) affects a given phenotype via concomitant down-regulation of its entire repertoire of targets or instead by suppression of only a modest subset of effectors. We demonstrate that inhibition of breast cancer metastasis by miR-31—a miRNA predicted to modulate >200 mRNAs—can be entirely explained by miR-31's pleiotropic regulation of three targets. Thus, concurrent re-expression of integrin-α5, radixin, and RhoA abrogates miR-31-imposed metastasis suppression. These effectors influence distinct steps of the metastatic process. Our findings have implications concerning the importance of pleiotropy for the biological actions of miRNAs and provide mechanistic insights into metastasis.
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Footnotes
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↵5 Corresponding author.
E-MAIL weinberg{at}wi.mit.edu; FAX (617) 258-5213.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1832709.
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Supplemental material is available at http://www.genesdev.org.
- Received June 15, 2009.
- Accepted September 24, 2009.
- Copyright © 2009 by Cold Spring Harbor Laboratory Press
