Vaklavas Christos, Blume Scott W, Grizzle William E
Department of Medicine, Division of Hematology/Oncology, University of Alabama at Birmingham, Birmingham, AL, United States.
Department of Anatomic Pathology, University of Alabama at Birmingham, Birmingham, AL, United States.
Front Oncol. 2017 Jul 26;7:158. doi: 10.3389/fonc.2017.00158. eCollection 2017.
Although transcript levels have been traditionally used as a surrogate measure of gene expression, it is increasingly recognized that the latter is extensively and dynamically modulated at the level of translation (messenger RNA to protein). Over the recent years, significant progress has been made in dissecting the complex posttranscriptional mechanisms that regulate gene expression. This advancement in knowledge came hand in hand with the progress made in the methodologies to study translation both at gene-specific as well as global genomic level. The majority of translational control is exerted at the level of initiation; nonetheless, protein synthesis can be modulated at the level of translation elongation, termination, and recycling. Sequence and structural elements and epitranscriptomic modifications of individual transcripts allow for dynamic gene-specific modulation of translation. Cancer cells usurp the regulatory mechanisms that govern translation to carry out translational programs that lead to the phenotypic hallmarks of cancer. Translation is a critical nexus in neoplastic transformation. Multiple oncogenes and signaling pathways that are activated, upregulated, or mutated in cancer converge on translation and their transformative impact "bottlenecks" at the level of translation. Moreover, this translational dysregulation allows cancer cells to adapt to a diverse array of stresses associated with a hostile microenviroment and antitumor therapies. All elements involved in the process of translation, from the transcriptional template, the components of the translational machinery, to the proteins that interact with the transcriptome, have been found to be qualitatively and/or quantitatively perturbed in cancer. This review discusses the regulatory mechanisms that govern translation in normal cells and how translation becomes dysregulated in cancer leading to the phenotypic hallmarks of malignancy. We also discuss how dysregulated mediators or components of translation can be utilized as biomarkers with potential diagnostic, prognostic, or predictive significance. Such biomarkers have the potential advantage of uniform applicability in the face of inherent tumor heterogeneity and deoxyribonucleic acid instability. As translation becomes increasingly recognized as a process gone awry in cancer and agents are developed to target it, the utility and significance of these potential biomarkers is expected to increase.
尽管传统上转录本水平一直被用作基因表达的替代指标，但人们越来越认识到，基因表达在翻译水平（信使核糖核酸到蛋白质）受到广泛而动态的调控。近年来，在剖析调控基因表达的复杂转录后机制方面取得了重大进展。这一知识的进步与在基因特异性以及全基因组水平研究翻译的方法学进展齐头并进。大多数翻译控制在起始水平发挥作用；尽管如此，蛋白质合成也可以在翻译延伸、终止和再循环水平进行调控。单个转录本的序列和结构元件以及表观转录组修饰允许对翻译进行动态的基因特异性调控。癌细胞篡夺了控制翻译的调控机制，以执行导致癌症表型特征的翻译程序。翻译是肿瘤转化中的关键环节。在癌症中被激活、上调或突变的多个癌基因和信号通路汇聚于翻译过程，它们的转化影响在翻译水平形成“瓶颈”。此外，这种翻译失调使癌细胞能够适应与恶劣微环境和抗肿瘤治疗相关的各种应激。在癌症中，从转录模板、翻译机器的组成部分到与转录组相互作用的蛋白质，参与翻译过程的所有元件在质量和/或数量上都被发现受到干扰。本综述讨论了正常细胞中控制翻译的调控机制，以及翻译在癌症中如何失调从而导致恶性肿瘤的表型特征。我们还讨论了失调的翻译介质或组分如何能够用作具有潜在诊断、预后或预测意义的生物标志物。面对内在的肿瘤异质性和脱氧核糖核酸不稳定性，此类生物标志物具有统一适用性的潜在优势。随着翻译越来越被认为是癌症中出现问题的一个过程，并且针对它的药物也在开发，这些潜在生物标志物的效用和意义有望增加。
