An Extensive MicroRNA-mediated Network of RNA-RNA Interactions Regulates Established Oncogenic Pathways in Glioblastoma

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2011 Oct 18

PMID 22000015

Citations 410

Authors

Pavel Sumazin

Xuerui Yang

Hua-Sheng Chiu

Wei-Jen Chung

Archana Iyer

David Llobet-Navas

Presha Rajbhandari

Mukesh Bansal

Paolo Guarnieri

Jose Silva

Andrea Califano

Affiliations

Soon will be listed here.

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.

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