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

By Pavel Sumazin, Xuerui Yang, Hua-Sheng Chiu, W. Chung, A. Iyer, David Llobet-Navás, Presha Rajbhandari, Mukesh Bansal, P. Guarnieri, Jose M. Silva and 1 more. Cell, 2011

710 citations recorded by the source corpus.

Summary By analyzing gene expression data in gliobastoma in combination with matched microRNA profiles, we have uncovered a post-transcriptional regulation layer of surprising magnitude, comprising over 248,000 microRNA (miR)-mediated interactions. These include ~7,000 genes whose transcripts act as miR ‘sponges’ and 148 genes that act through alternative, non-sponge interactions. Biochemical analyses in cell lines confirmed that this network regulates established drivers of tumor initiation and subtype, including PTEN, PDGFRA, RB1, VEGFA, STAT3, and RUNX1, suggesting that these interactions mediate crosstalk between canonical oncogenic pathways. RNA silencing of 13 microRNA-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, this miR-mediated network provides a mechanistic, experimentally validated rationale for the loss of PTEN expression in a large number of glioma samples with an intact PTEN locus.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/f4c27ba974f7d54fc47bb13732f10154ca180bea

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Citations in the corpus

The Somatic Genomic Landscape of Glioblastoma (2013, background): “ceRNAs are mRNAs coregulated in trans by a common miR (Sumazin et al., 2011; Tay et al., 2011).”
Roles for microRNAs in conferring robustness to biological processes. (2012, background): “Recently there have been reports of endogenous transcripts that appear to act as natural miRNA decoys, called ‘‘competitive endogenous RNAs’’ (ceRNAs) (Poliseno et al., 2010; Cesana et al., 2011; Karreth et al., 2011; Sumazin et al., 2011; Tay et al., 2011).”
Network-based inference of protein activity helps functionalize the genetic landscape of cancer (2016, background): “2f), making VIPER appropriate for the analysis of low-depth RNAseq profiles.”
A MicroRNA Superfamily Regulates Nucleotide Binding Site–Leucine-Rich Repeats and Other mRNAs[W][OA] (2012, background): “There are precedents for regulation of miRNAs by target mimics in both plant (Franco-Zorrilla et al., 2007) and animal systems (Cesana et al., 2011; Karreth et al., 2011; Sumazin et al., 2011; Tay et al., 2011).”
In vivo identification of tumor suppressive PTEN ceRNAs in an oncogenic BRAF-induced mouse model of melanoma (2011, positive): “Our findings of a microRNA-mediated andMRE-dependent gene regulatory ceRNA dimension are corroborated by two other studies demonstrating ceRNA activity for protein coding (Sumazin et al., 2011 [this issue of Cell]) and noncoding RNA (Cesana et al., 2011 [this issue of Cell]) molecules.”
A Long Noncoding RNA Controls Muscle Differentiation by Functioning as a Competing Endogenous RNA (2011, positive): “Recent data suggest that coding and noncoding RNAs can regulate one another through their ability to compete for miRNA binding; these molecules have been termed competing endogenous RNA (ceRNA, Salmena et al., 2011). ceRNAs can sequester miRNAs, thereby protecting their target RNAs from repression (”