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Cell. 2011 Oct 14;147(2):370-81. doi: 10.1016/j.cell.2011.09.041.

An extensive microRNA-mediated network of RNA-RNA interactions regulates established oncogenic pathways in glioblastoma.

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  • 1Columbia Initiative in Systems Biology, Columbia University, New York, NY 10032, USA.

Abstract

By analyzing gene expression data in glioblastoma in combination with matched microRNA profiles, we have uncovered a posttranscriptional regulation layer of surprising magnitude, comprising more than 248,000 microRNA (miR)-mediated interactions. These include ∼7,000 genes whose transcripts act as miR "sponges" and 148 genes that act through alternative, nonsponge interactions. Biochemical analyses in cell lines confirmed that this network regulates established drivers of tumor initiation and subtype implementation, including PTEN, PDGFRA, RB1, VEGFA, STAT3, and RUNX1, suggesting that these interactions mediate crosstalk between canonical oncogenic pathways. siRNA silencing of 13 miR-mediated PTEN regulators, whose locus deletions are predictive of PTEN expression variability, was sufficient to downregulate PTEN in a 3'UTR-dependent manner and to increase tumor cell growth rates. Thus, miR-mediated interactions provide a mechanistic, experimentally validated rationale for the loss of PTEN expression in a large number of glioma samples with an intact PTEN locus.

Copyright © 2011 Elsevier Inc. All rights reserved.

Comment in

  • RNA: a new layer of regulation. [Nat Rev Mol Cell Biol. 2011]
  • Regulatory RNA: layer by layer. [Nat Rev Genet. 2011]
  • Epigenetics. Layer by layer. [Nat Rev Cancer. 2011]
  • ceRNAs: miRNA target mimic mimics. [Cell. 2011]
PMID:
22000015
[PubMed - indexed for MEDLINE]
PMCID:
PMC3214599
Free PMC Article

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