Department of General Surgery, Zhongshan Hospital, Fudan University & State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China.
Liver Cancer Institute, Zhongshan Hospital, Fudan University & State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China; Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai, 200032, China.
Cancer Lett. 2021 Mar 31;501:83-104. doi: 10.1016/j.canlet.2020.11.043. Epub 2020 Dec 10.
More than 95% of all human genes are alternatively spliced after transcription, which enriches the diversity of proteins and regulates transcript and/or protein levels. The splicing isoforms produced from the same gene can manifest distinctly, even exerting opposite effects. Mounting evidence indicates that the alternative splicing (AS) mechanism is ubiquitous in various cancers and drives the generation and maintenance of various hallmarks of cancer, such as enhanced proliferation, inhibited apoptosis, invasion and metastasis, and angiogenesis. Splicing factors (SFs) play pivotal roles in the recognition of splice sites and the assembly of spliceosomes during AS. In this review, we mainly discuss the similarities and differences of SF domains, the details of SF function in AS, the effect of SF-driven pathological AS on different hallmarks of cancer, and the main drivers of SF expression level and subcellular localization. In addition, we briefly introduce the application prospects of targeted therapeutic strategies, including small-molecule inhibitors, siRNAs and splice-switching oligonucleotides (SSOs), from three perspectives (drivers, SFs and pathological AS). Finally, we share our insights into the potential direction of research on SF-centric AS-related regulatory networks.
超过 95%的人类基因在转录后会进行选择性剪接，这丰富了蛋白质的多样性，并调节转录本和/或蛋白质水平。同一基因产生的剪接异构体表现明显不同，甚至产生相反的效果。越来越多的证据表明，选择性剪接（AS）机制在各种癌症中普遍存在，并推动了各种癌症特征的产生和维持，如增强的增殖、抑制的凋亡、侵袭和转移以及血管生成。剪接因子（SFs）在 AS 过程中识别剪接位点和剪接体组装中发挥关键作用。在这篇综述中，我们主要讨论 SF 结构域的异同、SF 在 AS 中的功能细节、SF 驱动的病理性 AS 对不同癌症特征的影响以及 SF 表达水平和亚细胞定位的主要驱动因素。此外，我们还简要介绍了靶向治疗策略的应用前景，包括从小分子抑制剂、siRNAs 和剪接转换寡核苷酸（SSOs）三个方面（驱动因素、SF 和病理性 AS）。最后，我们分享了我们对以 SF 为中心的 AS 相关调控网络的潜在研究方向的见解。
