Cancer Initiation and Tumor Cell Identity, Cancer Research Center of Lyon, Université de Lyon, Université Claude Bernard Lyon 1, Inserm U1052, CNRS UMR5286 Centre Léon Bérard, 69008 Lyon, France.
Institute of Pathology EST, Hospices Civils de Lyon, Site-Est Groupement Hospitalier- Est, 69677 Bron, France.
Cells. 2020 Oct 27;9(11):2361. doi: 10.3390/cells9112361.
Many studies have focused on understanding the regulation and functions of aberrant protein synthesis in colorectal cancer (CRC), leaving the ribosome, its main effector, relatively underappreciated in CRC. The production of functional ribosomes is initiated in the nucleolus, requires coordinated ribosomal RNA (rRNA) processing and ribosomal protein (RP) assembly, and is frequently hyperactivated to support the needs in protein synthesis essential to withstand unremitting cancer cell growth. This elevated ribosome production in cancer cells includes a strong alteration of ribosome biogenesis homeostasis that represents one of the hallmarks of cancer cells. None of the ribosome production steps escape this cancer-specific dysregulation. This review summarizes the early and late steps of ribosome biogenesis dysregulations described in CRC cell lines, intestinal organoids, CRC stem cells and mouse models, and their possible clinical implications. We highlight how this cancer-related ribosome biogenesis, both at quantitative and qualitative levels, can lead to the synthesis of ribosomes favoring the translation of mRNAs encoding hyperproliferative and survival factors. We also discuss whether cancer-related ribosome biogenesis is a mere consequence of cancer progression or is a causal factor in CRC, and how altered ribosome biogenesis pathways can represent effective targets to kill CRC cells. The association between exacerbated CRC cell growth and alteration of specific steps of ribosome biogenesis is highlighted as a key driver of tumorigenesis, providing promising perspectives for the implementation of predictive biomarkers and the development of new therapeutic drugs.
许多研究都集中在了解结直肠癌（CRC）中异常蛋白质合成的调控和功能，而核糖体作为其主要效应器，在 CRC 中的研究相对较少。功能性核糖体的产生始于核仁，需要协调核糖体 RNA（rRNA）加工和核糖体蛋白（RP）组装，并且经常过度激活以支持抵抗不断增长的癌细胞生长所需的蛋白质合成。癌细胞中核糖体的产生增加包括核糖体生物发生稳态的强烈改变，这是癌细胞的标志之一。核糖体产生的所有步骤都无法逃脱这种特异性失调。本文总结了在 CRC 细胞系、肠类器官、CRC 干细胞和小鼠模型中描述的核糖体生物发生失调的早期和晚期步骤，及其可能的临床意义。我们强调了这种与癌症相关的核糖体生物发生，无论是在定量还是定性水平上，都可以导致有利于翻译编码过度增殖和存活因子的 mRNA 的核糖体的合成。我们还讨论了与癌症相关的核糖体生物发生是癌症进展的必然结果，还是 CRC 的因果因素，以及改变的核糖体生物发生途径如何成为杀死 CRC 细胞的有效靶点。强调加剧的 CRC 细胞生长与核糖体生物发生特定步骤的改变之间的关联是肿瘤发生的关键驱动因素，为实施预测性生物标志物和开发新的治疗药物提供了有希望的前景。
