Targeting nonsense-mediated mRNA decay in colorectal cancers with microsatellite instability

Area of Science:

• Molecular Biology
• Oncology
• Genetics

Background:

• Nonsense-mediated mRNA decay (NMD) degrades mRNAs with premature termination codons (PTCs).
• The role of NMD in cancer, particularly colorectal cancer (CRC), remains largely unclear.
• Microsatellite instability (MSI) in CRC is associated with increased PTC-containing mRNAs.

Purpose of the Study:

• To investigate the functional impact of NMD in MSI colorectal cancers.
• To identify potential therapeutic strategies targeting NMD in CRC.

Main Methods:

• Comparative analysis of NMD activity and expression in MSI versus microsatellite stable (MSS) CRC.
• Suppression of NMD activity and assessment of downstream mRNA and protein changes.
• In vivo inhibition of NMD using amlexanox in mouse models of CRC.

Main Results:

• MSI CRC exhibits elevated levels of NMD activators (UPF1/2, SMG1/6/7) compared to MSS CRC.
• NMD suppression in MSI CRC leads to re-expression of numerous PTC mRNAs, including those encoding potentially oncogenic mutant proteins (e.g., HSP110DE9).
• In vivo NMD inhibition with amlexanox significantly reduced MSI tumor growth but not MSS tumor growth.

Conclusions:

• NMD plays a significant role in promoting tumorigenesis in MSI colorectal cancers.
• Targeting NMD represents a promising personalized therapeutic strategy for MSI CRC.