Related Experiment Videos
miRNA Mediated Noise Making of 3'UTR Mutations in Cancer
Wei Wu1, Lingxiang Wu2, Mengyan Zhu3
1Department of Bioinformatics, Nanjing Medical University, Nanjing 211166, China. wuwei.bioinformatics@gmail.com.
Abstract:
Somatic mutations in 3'-untranslated regions (3'UTR) do not alter amino acids and are considered to be silent in cancers. We found that such mutations can promote tumor progression by altering microRNA (miRNA) targeting efficiency and consequently affecting miRNA⁻mRNA interactions. We identified 67,159 somatic mutations located in the 3'UTRs of messenger RNAs (mRNAs) which can alter miRNA⁻mRNA interactions (functional somatic mutations, funcMutations), and 69.3% of these funcMutations (the degree of energy change > 12 kcal/mol) were identified to significantly promote loss of miRNA-mRNA binding. By integrating mRNA expression profiles of 21 cancer types, we found that the expression of target genes was positively correlated with the loss of absolute affinity level and negatively correlated with the gain of absolute affinity level. Functional enrichment analysis revealed that genes carrying funcMutations were significantly enriched in the MAPK and WNT signaling pathways, and analysis of regulatory modules identified eighteen miRNA modules involved with similar cellular functions. Our findings elucidate a complex relationship between miRNA, mRNA, and mutations, and suggest that 3'UTR mutations may play an important role in tumor development.
Insights
Somatic mutations in 3' untranslated regions (3'UTR) can drive cancer progression by disrupting microRNA (miRNA) binding to messenger RNAs (mRNAs). These functional mutations impact gene expression and signaling pathways crucial for tumor development.
Area of Science:
- Genomics
- Cancer Biology
- Molecular Biology
Background:
- Somatic mutations in 3' untranslated regions (3'UTR) are often considered silent as they do not alter amino acid sequences.
- MicroRNAs (miRNAs) regulate gene expression post-transcriptionally by binding to messenger RNAs (mRNAs).
- Dysregulation of miRNA-mRNA interactions is implicated in various diseases, including cancer.
Purpose of the Study:
- To investigate the functional impact of 3'UTR somatic mutations on miRNA targeting efficiency in cancer.
- To identify specific 3'UTR mutations that alter miRNA-mRNA interactions and affect tumor progression.
- To explore the downstream consequences of these mutations on gene expression and signaling pathways.
Main Methods:
- Identification and characterization of somatic mutations within 3'UTRs across 21 cancer types.
- Computational analysis to predict the impact of mutations on miRNA binding affinity (energy change > 12 kcal/mol).
- Integration of mutation data with mRNA expression profiles and functional enrichment analysis (e.g., MAPK, WNT pathways).
Main Results:
- Over 67,000 functional somatic mutations (funcMutations) in 3'UTRs were identified, significantly altering miRNA-mRNA interactions.
- 69.3% of identified funcMutations promoted a loss of miRNA-mRNA binding affinity.
- Genes with funcMutations were enriched in key cancer-related signaling pathways, including MAPK and WNT.
- Eighteen miRNA modules were identified as potentially involved in regulating these mutated genes.
Conclusions:
- 3'UTR somatic mutations are not silent and can actively promote tumor progression.
- These mutations disrupt crucial miRNA-mRNA interactions, leading to altered gene expression.
- Understanding the role of 3'UTR mutations in miRNA regulation offers new insights into cancer development and potential therapeutic targets.