title: An extensive microRNA-mediated network of RNA-RNA interactions regulates established oncogenic pathways in glioblastoma.
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.
authors: Columbia Initiative in Systems Biology, Columbia University, New York, NY 10032, USA.
authors: Pavel
authors: P
authors: Sumazin
authors: Xuerui
authors: X
authors: Yang
authors: Hua-Sheng
authors: HS
authors: Chiu
authors: Wei-Jen
authors: WJ
authors: Chung
authors: Archana
authors: A
authors: Iyer
authors: David
authors: D
authors: Llobet-Navas
authors: Presha
authors: P
authors: Rajbhandari
authors: Mukesh
authors: M
authors: Bansal
authors: Paolo
authors: P
authors: Guarnieri
authors: Jose
authors: J
authors: Silva
authors: Andrea
authors: A
authors: Califano
mesh_terms: D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D015999:Multivariate Analysis; D009857:Oncogenes; D051059:PTEN Phosphohydrolase / Q000235:genetics; D034622:RNA Interference
chemical_list: D035683:MicroRNAs; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human