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High-throughput Screening for Chemical Modulators of Post-transcriptionally Regulated Genes
Published on: March 3, 2015
High-throughput validation of ceRNA regulatory networks
Hua-Sheng Chiu1, María Rodríguez Martínez2, Mukesh Bansal3
1Texas Children's Cancer Center and Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Background:
MicroRNAs (miRNAs) play multiple roles in tumor biology. Interestingly, reports from multiple groups suggest that miRNA targets may be coupled through competitive stoichiometric sequestration. Specifically, computational models predicted and experimental assays confirmed that miRNA activity is dependent on miRNA target abundance, and consequently, changes in the abundance of some miRNA targets lead to changes to the regulation and abundance of their other targets. The resulting indirect regulatory influence between miRNA targets resembles competition and has been dubbed competitive endogenous RNA (ceRNA). Recent studies have questioned the physiological relevance of ceRNA interactions, our ability to accurately predict these interactions, and the number of genes that are impacted by ceRNA interactions in specific cellular contexts.
Results:
To address these concerns, we reverse engineered ceRNA networks (ceRNETs) in breast and prostate adenocarcinomas using context-specific TCGA profiles, and tested whether ceRNA interactions can predict the effects of RNAi-mediated gene silencing perturbations in PC3 and MCF7 cells._ENREF_22 Our results, based on tests of thousands of inferred ceRNA interactions that are predicted to alter hundreds of cancer genes in each of the two tumor contexts, confirmed statistically significant effects for half of the predicted targets.
Conclusions:
Our results suggest that the expression of a significant fraction of cancer genes may be regulated by ceRNA interactions in each of the two tumor contexts.
Insights
Competitive endogenous RNA (ceRNA) interactions regulate gene expression in cancer. This study confirms ceRNA networks significantly impact hundreds of cancer genes, suggesting broad regulatory roles in tumor biology.
Area of Science:
- Molecular Biology
- Genomics
- Cancer Research
Background:
- MicroRNAs (miRNAs) are crucial in tumor biology.
- Competitive endogenous RNA (ceRNA) interactions involve miRNA target sequestration.
- ceRNA interactions' physiological relevance and predictive accuracy are debated.
Purpose of the Study:
- To reverse engineer ceRNA networks (ceRNETs) in breast and prostate cancers.
- To test if ceRNA interactions predict gene silencing effects.
- To assess the impact of ceRNA interactions on cancer genes.
Main Methods:
- Utilized TCGA profiles to build context-specific ceRNETs.
- Employed RNAi-mediated gene silencing in PC3 and MCF7 cells.
- Validated thousands of inferred ceRNA interactions.
Main Results:
- ceRNETs were successfully reverse engineered for breast and prostate cancers.
- ceRNA interactions significantly predicted gene silencing effects for half of the tested targets.
- Hundreds of cancer genes were identified as potentially regulated by ceRNA interactions.
Conclusions:
- A significant fraction of cancer genes are likely regulated by ceRNA interactions.
- ceRNA networks play a substantial role in regulating gene expression within tumor contexts.
- This study provides evidence for the physiological relevance of ceRNA interactions in cancer.
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