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Nucleic Acids Res. 2018 May 18;46(9):4354-4369. doi: 10.1093/nar/gky286.

The number of titrated microRNA species dictates ceRNA regulation.

Author information

1
Texas Children's Cancer Center and Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
2
IBM Research-Zurich, 8803 Rüschlikon, Zurich, Switzerland.
3
Department of Systems Biology, Institute for Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Center for Computational Biology and Bioinformatics, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.
4
Department of Pathology and Cell Biology, Institute for Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Center for Computational Biology and Bioinformatics, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.
5
Bellvitge Biomedical Research Institute (IDIBELL), Gran via de l'Hospitalet, 199, L'Hospitalet de Llobregat 08908, Spain.
6
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
7
MOE Key Laboratory of Bioinformatics, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
8
Department of Biomedical Informatics, and Department of Biochemistry and Molecular Biophysics, and Institute for Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Center for Computational Biology and Bioinformatics, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.

Abstract

microRNAs (miRNAs) play key roles in cancer, but their propensity to couple their targets as competing endogenous RNAs (ceRNAs) has only recently emerged. Multiple models have studied ceRNA regulation, but these models did not account for the effects of co-regulation by miRNAs with many targets. We modeled ceRNA and simulated its effects using established parameters for miRNA/mRNA interaction kinetics while accounting for co-regulation by multiple miRNAs with many targets. Our simulations suggested that co-regulation by many miRNA species is more likely to produce physiologically relevant context-independent couplings. To test this, we studied the overlap of inferred ceRNA networks from four tumor contexts-our proposed pan-cancer ceRNA interactome (PCI). PCI was composed of interactions between genes that were co-regulated by nearly three-times as many miRNAs as other inferred ceRNA interactions. Evidence from expression-profiling datasets suggested that PCI interactions are predictive of gene expression in 12 independent tumor- and non-tumor contexts. Biochemical assays confirmed ceRNA couplings for two PCI subnetworks, including oncogenes CCND1, HIF1A and HMGA2, and tumor suppressors PTEN, RB1 and TP53. Our results suggest that PCI is enriched for context-independent interactions that are coupled by many miRNA species and are more likely to be context independent.

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