NMD Inhibition Reduces Tumorigenicity

Evidence exists for nonsense-mediated mRNA decay (NMD) promoting tumorigenicity as well as suppressing it. The Mühlemann lab and collaborators used human HT1080 fibrosarcoma cells to shed further light on the role of NMD in cancer. They created cells in which the NMD factor SMG7 was knocked out by CRISPR/Cas leading to strong NMD inhibition and corresponding rescue cells in which SMG7 expression was restored. Through assessing tumorigenicity in cellular experiments as well as xenografting tumors to mice, they could show that NMD inhibtion lowers tumorigenicity. Part of this effect is due to lower levels of the matrix mettaloprotease 9 (MMP9). Their findings were published in the article "Inhibition of nonsense-mediated mRNA decay reduces the tumorigenicity of human fibrosarcoma cells" in Nucleic Acids Research Cancer.

Nonsense-mediated mRNA decay (NMD) is a eukaryotic RNA decay pathway with roles in cellular stress responses, differentiation, and viral defense. It functions in both quality control and post-transcriptional regulation of gene expression. NMD has also emerged as a modulator of cancer progression, although available evidence supports both a tumor suppressor and a pro-tumorigenic role, depending on the model. To further investigate the role of NMD in cancer, we knocked out the NMD factor SMG7 in the HT1080 human fibrosarcoma cell line, resulting in suppression of NMD function. We then compared the oncogenic properties of the parental cell line, the SMG7-knockout, and a rescue cell line in which we re-introduced both isoforms of SMG7. We also tested the effect of a drug inhibiting the NMD factor SMG1 to distinguish NMD-dependent effects from putative NMD-independent functions of SMG7. Using cell-based assays and a mouse xenograft tumor model, we showed that suppression of NMD function severely compromises the oncogenic phenotype. Molecular pathway analysis revealed that NMD suppression strongly reduces matrix metalloprotease 9 (MMP9) expression and that MMP9 re-expression partially rescues the oncogenic phenotype. Since MMP9 promotes cancer cell migration and invasion, metastasis and angiogenesis, its downregulation may contribute to the reduced tumorigenicity of NMD-suppressed cells. Collectively, our results highlight the potential value of NMD inhibition as a therapeutic approach.

Read the Publication in NAR Cancer (Open Access)

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Abstract, figure and title from Nasif et al (2023) NAR Cancer published under a CC BY-NC 4.0 license.