Skotheim Rolf I, Nees Matthias
Department of Cancer Prevention, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway.
Int J Biochem Cell Biol. 2007;39(7-8):1432-49. doi: 10.1016/j.biocel.2007.02.016. Epub 2007 Mar 1.
Pre-messenger RNA splicing is a fine-tuned process that generates multiple functional variants from individual genes. Various cell types and developmental stages regulate alternative splicing patterns differently in their generation of specific gene functions. In cancers, splicing is significantly altered, and understanding the underlying mechanisms and patterns in cancer will shed new light onto cancer biology. Cancer-specific transcript variants are promising biomarkers and targets for diagnostic, prognostic, and treatment purposes. In this review, we explore how alternative splicing cannot simply be considered as noise or an innocent bystander, but is actively regulated or deregulated in cancers. A special focus will be on aspects of cell biology and biochemistry of alternative splicing in cancer cells, addressing differences in splicing mechanisms between normal and malignant cells. The systems biology of splicing is only now applied to the field of cancer research. We explore functional annotations for some of the most intensely spliced gene classes, and provide a literature mining and clustering that reflects the most intensely investigated genes. A few well-established cancer-specific splice events, such as the CD44 antigen, are used to illustrate the potential behind the exploration of the mechanisms of their regulation. Accordingly, we describe the functional connection between the regulatory machinery (i.e., the spliceosome and its accessory proteins) and their global impact on qualitative transcript variation that are only now emerging from the use of genomic technologies such as microarrays. These studies are expected to open an entirely new level of genetic information that is currently still poorly understood.
信使前体RNA剪接是一个经过精细调控的过程，它能从单个基因产生多种功能变体。在产生特定基因功能的过程中，各种细胞类型和发育阶段对可变剪接模式的调控方式各不相同。在癌症中，剪接受显著改变，了解癌症中的潜在机制和模式将为癌症生物学带来新的启示。癌症特异性转录变体有望成为用于诊断、预后和治疗目的的生物标志物和靶点。在本综述中，我们探讨了可变剪接如何不能简单地被视为噪音或无辜的旁观者，而是在癌症中受到积极调控或失调。特别关注将集中在癌细胞中可变剪接的细胞生物学和生物化学方面，探讨正常细胞和恶性细胞之间剪接机制的差异。剪接的系统生物学目前才应用于癌症研究领域。我们探索了一些剪接最活跃的基因类别的功能注释，并提供了反映研究最深入的基因的文献挖掘和聚类。一些已确立的癌症特异性剪接事件，如CD44抗原，被用来阐明探索其调控机制背后的潜力。因此，我们描述了调控机制（即剪接体及其辅助蛋白）与其对转录本定性变异的全局影响之间的功能联系，而这些影响目前才通过微阵列等基因组技术得以显现。这些研究有望开启一个目前仍了解甚少的全新遗传信息层面。
