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Nonsense-mediated RNA decay and its bipolar function in cancer
Gonçalo Nogueira1,2, Rafael Fernandes1,2, Juan F García-Moreno1,2
1Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge, 1649-016, Lisbon, Portugal.
Abstract:
Nonsense-mediated decay (NMD) was first described as a quality-control mechanism that targets and rapidly degrades aberrant mRNAs carrying premature termination codons (PTCs). However, it was found that NMD also degrades a significant number of normal transcripts, thus arising as a mechanism of gene expression regulation. Based on these important functions, NMD regulates several biological processes and is involved in the pathophysiology of a plethora of human genetic diseases, including cancer. The present review aims to discuss the paradoxical, pro- and anti-tumorigenic roles of NMD, and how cancer cells have exploited both functions to potentiate the disease. Considering recent genetic and bioinformatic studies, we also provide a comprehensive overview of the present knowledge of the advantages and disadvantages of different NMD modulation-based approaches in cancer therapy, reflecting on the challenges imposed by the complexity of this disease. Furthermore, we discuss significant advances in the recent years providing new perspectives on the implications of aberrant NMD-escaping frameshifted transcripts in personalized immunotherapy design and predictive biomarker optimization. A better understanding of how NMD differentially impacts tumor cells according to their own genetic identity will certainly allow for the application of novel and more effective personalized treatments in the near future.
Insights
Nonsense-mediated decay (NMD) regulates gene expression and impacts cancer. This review explores NMD's dual roles in tumor development and its therapeutic potential, highlighting personalized treatment strategies.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- Nonsense-mediated decay (NMD) initially identified as a mRNA quality control pathway targeting aberrant transcripts with premature termination codons (PTCs).
- Emerging evidence reveals NMD's crucial role in regulating normal gene expression and its involvement in various biological processes and human diseases, including cancer.
Purpose of the Study:
- To review the complex, dual roles of NMD in cancer, encompassing both its pro- and anti-tumorigenic functions.
- To analyze how cancer cells leverage NMD pathways to promote disease progression.
- To provide an overview of NMD modulation strategies for cancer therapy, considering genetic and bioinformatic insights.
Main Methods:
- Literature review integrating genetic and bioinformatic studies.
- Analysis of NMD's involvement in cancer pathophysiology.
- Evaluation of NMD modulation-based therapeutic approaches.
Main Results:
- NMD exhibits paradoxical roles in cancer, acting as both a tumor promoter and suppressor.
- Cancer cells exploit NMD functions to enhance disease progression.
- NMD-escaping frameshifted transcripts offer new avenues for personalized immunotherapy and biomarker development.
Conclusions:
- Understanding NMD's differential impact on tumor cells based on their genetic makeup is key to developing effective, personalized cancer treatments.
- NMD modulation presents a promising therapeutic strategy, but challenges related to cancer complexity need addressing.
- Aberrant NMD transcripts hold potential for advancing personalized immunotherapy and optimizing predictive biomarkers.
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