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The number of titrated microRNA species dictates ceRNA regulation

Hua-Sheng Chiu1, María Rodríguez Martínez2, Elena V Komissarova3,4

  • 1Texas Children's Cancer Center and Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.

Nucleic Acids Research
|April 24, 2018
PubMed

Insights

Competing endogenous RNA (ceRNA) networks are crucial in cancer. This study reveals that interactions regulated by numerous microRNAs (miRNAs) are more likely to be context-independent and physiologically relevant.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • MicroRNAs (miRNAs) are key regulators in cancer.
  • Competing endogenous RNA (ceRNA) networks describe miRNA-target interactions.
  • Existing ceRNA models do not fully account for miRNA co-regulation of multiple targets.

Purpose of the Study:

  • To develop and validate a model for ceRNA regulation that incorporates co-regulation by multiple miRNAs.
  • To identify context-independent ceRNA interactions.
  • To construct a pan-cancer ceRNA interactome (PCI).

Main Methods:

  • Modeled ceRNA regulation using miRNA/mRNA interaction kinetics.
  • Simulated effects of co-regulation by multiple miRNAs with numerous targets.
  • Inferred ceRNA networks from four tumor contexts.
  • Analyzed gene expression data from 12 independent tumor and non-tumor contexts.
  • Performed biochemical assays to confirm ceRNA couplings.

Main Results:

  • Simulations indicated that extensive miRNA co-regulation favors context-independent ceRNA couplings.
  • The proposed pan-cancer ceRNA interactome (PCI) comprises interactions co-regulated by significantly more miRNAs than other interactions.
  • PCI interactions accurately predict gene expression across diverse contexts.
  • Biochemical assays validated ceRNA couplings for key oncogenes and tumor suppressors within PCI subnetworks.

Conclusions:

  • The pan-cancer ceRNA interactome (PCI) is enriched for context-independent ceRNA interactions.
  • These interactions are predominantly driven by co-regulation from multiple miRNA species.
  • PCI represents a robust framework for understanding miRNA-mediated gene regulation in cancer.

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