TY - JOUR
T1 - An extensive MicroRNA-mediated network of RNA-RNA interactions regulates established oncogenic pathways in glioblastoma
AU - Sumazin, Pavel
AU - Yang, Xuerui
AU - Chiu, Hua Sheng
AU - Chung, Wei Jen
AU - Iyer, Archana
AU - Llobet-Navas, David
AU - Rajbhandari, Presha
AU - Bansal, Mukesh
AU - Guarnieri, Paolo
AU - Silva, Jose
AU - Califano, Andrea
N1 - Funding Information:
We thank James Chi-ping Chen and Mariano J. Alvarez for critical discussion and Katia Basso, Francesco Niola, Antonio Iavarone, and Anna Lasorella for support and suggestions. We would also like to acknowledge the generous funding provided by the NIH under the following grant awards: (1) Roadmap grant for a Center for the Multiscale Analysis of Genetic Networks (MAGNet) (U54CA121852), (2) Genetic Network Inference with Combinational Phenotypes (R01CA109755), and (3) In Silico Research Centre of Excellence NCI-caBIG 29XS192. P.S. and A.C. conceived and supervised the project and participated in its computational and experimental design. P.S., H.-S.C, W.-J.C., M.B., and P.G. designed and implemented the computational methods. P.S., X.Y., H.-S.C., and W.-J.C. analyzed data. P.S., X.Y., J.S., and A.C. designed the experimental assays. X.Y., A.I., D.L.-N., and P.R. performed the experiments. P.S., X.Y., H.-S.C., and A.C. wrote the paper.
PY - 2011/10/14
Y1 - 2011/10/14
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=80054689794&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2011.09.041
DO - 10.1016/j.cell.2011.09.041
M3 - Article
C2 - 22000015
AN - SCOPUS:80054689794
SN - 0092-8674
VL - 147
SP - 370
EP - 381
JO - Cell
JF - Cell
IS - 2
ER -