Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Diego, La Jolla, CA, USA.
UCSD Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
Nat Rev Cancer. 2022 Aug;22(8):437-451. doi: 10.1038/s41568-022-00481-2. Epub 2022 May 27.
Nonsense-mediated RNA decay (NMD) is a highly conserved RNA turnover pathway that selectively degrades RNAs harbouring truncating mutations that prematurely terminate translation, including nonsense, frameshift and some splice-site mutations. Recent studies show that NMD shapes the mutational landscape of tumours by selecting for mutations that tend to downregulate the expression of tumour suppressor genes but not oncogenes. This suggests that NMD can benefit tumours, a notion further supported by the finding that mRNAs encoding immunogenic neoantigen peptides are typically targeted for decay by NMD. Together, this raises the possibility that NMD-inhibitory therapy could be of therapeutic benefit against many tumour types, including those with a high load of neoantigen-generating mutations. Complicating this scenario is the evidence that NMD can also be detrimental for many tumour types, and consequently tumours often have perturbed NMD. NMD may suppress tumour generation and progression by degrading subsets of specific normal mRNAs, including those encoding stress-response proteins, signalling factors and other proteins beneficial for tumours, as well as pro-tumour non-coding RNAs. Together, these findings suggest that NMD-modulatory therapy has the potential to provide widespread therapeutic benefit against diverse tumour types. However, whether NMD should be stimulated or repressed requires careful analysis of the tumour to be treated.
无意义介导的 RNA 衰减（NMD）是一种高度保守的 RNA 降解途径，可选择性地降解含有过早终止翻译的截断突变的 RNA，包括无义突变、移码突变和一些剪接位点突变。最近的研究表明，NMD 通过选择倾向于下调肿瘤抑制基因表达而不是癌基因表达的突变来塑造肿瘤的突变景观。这表明 NMD 可以使肿瘤受益，这一观点进一步得到了支持，即编码免疫原性新抗原肽的 mRNA 通常被 NMD 靶向降解。综上所述，这提出了一种可能性，即 NMD 抑制治疗可能对许多肿瘤类型具有治疗益处，包括那些具有大量产生新抗原突变的肿瘤类型。使这种情况复杂化的是有证据表明，NMD 也可能对许多肿瘤类型有害，因此肿瘤通常会出现 NMD 失调。NMD 可能通过降解特定正常 mRNA 的亚群来抑制肿瘤的发生和进展，包括那些编码应激反应蛋白、信号因子和其他对肿瘤有益的蛋白质的 mRNA，以及促肿瘤非编码 RNA。综上所述，这些发现表明，NMD 调节治疗有可能对多种肿瘤类型提供广泛的治疗益处。然而，是否应该刺激或抑制 NMD 需要仔细分析要治疗的肿瘤。
