抑制无义介导的 mRNA 衰变可降低人类纤维肉瘤细胞的致瘤性。

NAR Cancer Pub Date : 2023-09-06 eCollection Date: 2023-09-01 DOI:10.1093/narcan/zcad048
Sofia Nasif, Martino Colombo, Anne-Christine Uldry, Markus S Schröder, Simone de Brot, Oliver Mühlemann
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引用次数: 0

摘要

无义介导的 mRNA 降解(NMD)是真核生物的一种 RNA 降解途径,在细胞应激反应、分化和病毒防御中发挥作用。它在基因表达的质量控制和转录后调控中发挥作用。NMD 也已成为癌症进展的调控因子,但现有证据表明,根据不同的模型,NMD 既有抑制肿瘤的作用,也有促进致癌的作用。为了进一步研究 NMD 在癌症中的作用,我们敲除了 HT1080 人类纤维肉瘤细胞系中的 NMD 因子 SMG7,从而抑制了 NMD 的功能。然后,我们比较了亲代细胞系、SMG7 基因敲除细胞系和重新引入两种同工酶 SMG7 的拯救细胞系的致癌特性。我们还测试了抑制 NMD 因子 SMG1 的药物的效果,以区分 SMG7 的 NMD 依赖性效应和假定的 NMD 非依赖性功能。通过基于细胞的实验和小鼠异种移植肿瘤模型,我们发现抑制 NMD 功能会严重损害致癌表型。分子通路分析表明,抑制 NMD 会强烈降低基质金属蛋白酶 9(MMP9)的表达,而 MMP9 的重新表达可部分挽救致癌表型。由于 MMP9 能促进癌细胞的迁移和侵袭、转移和血管生成,因此它的下调可能有助于降低 NMD 抑制细胞的致瘤性。总之,我们的研究结果凸显了 NMD 抑制作为一种治疗方法的潜在价值。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Inhibition of nonsense-mediated mRNA decay reduces the tumorigenicity of human fibrosarcoma cells.

Inhibition of nonsense-mediated mRNA decay reduces the tumorigenicity of human fibrosarcoma cells.

Inhibition of nonsense-mediated mRNA decay reduces the tumorigenicity of human fibrosarcoma cells.

Inhibition of nonsense-mediated mRNA decay reduces the tumorigenicity of human fibrosarcoma cells.

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.

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