Chen Huiping, Tang Jingqun, Xiang Juanjuan
Hunan Key Laboratory of Early Diagnosis and Precise Treatment of Lung Cancer, The Second Xiangya Hospital, Central South University, Changsha 410013, China.
Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha 410078, China.
Biomolecules. 2025 May 29;15(6):789. doi: 10.3390/biom15060789.
Alternative splicing (AS) is a pivotal post-transcriptional mechanism that expands the functional diversity of the proteome by enabling a single gene to generate multiple mRNA and protein isoforms. This process, which involves the differential inclusion or exclusion of exons and introns, is tightly regulated by splicing factors (SFs), such as serine/arginine-rich proteins (SRs), heterogeneous nuclear ribonucleoproteins (hnRNPs), and RNA-binding motif (RBM) proteins. These factors recognize specific sequences, including 5' and 3' splice sites and branch points, to ensure precise splicing. While AS is essential for normal cellular function, its dysregulation is increasingly implicated in cancer pathogenesis. Aberrant splicing can lead to the production of oncogenic isoforms that promote tumorigenesis, metastasis, and resistance to therapy. Furthermore, such abnormalities can cause the loss of tumor-suppressing activity, thereby contributing to cancer development. Importantly, abnormal AS events can generate neoantigens, which are presented on tumor cell surfaces via major histocompatibility complex (MHC) molecules, suggesting novel targets for cancer immunotherapy. Additionally, splice-switching oligonucleotides (SSOs) have shown promise as therapeutic agents because they modulate splicing patterns to restore normal gene function or induce tumor-suppressive isoforms. This review explores the mechanisms of AS dysregulation in cancer, its role in tumor progression, and its potential as a therapeutic target. We also discuss innovative technologies, such as high-throughput sequencing and computational approaches, that are revolutionizing the study of AS in cancer. Finally, we address the challenges and future prospects of targeting AS for personalized cancer therapies, emphasizing its potential in precision medicine.
可变剪接（Alternative splicing，AS）是一种关键的转录后机制，它通过使单个基因产生多种mRNA和蛋白质异构体来扩展蛋白质组的功能多样性。这个过程涉及外显子和内含子的差异包含或排除，受到剪接因子（SFs）的严格调控，如富含丝氨酸/精氨酸的蛋白质（SRs）、异质性核核糖核蛋白（hnRNPs）和RNA结合基序（RBM）蛋白。这些因子识别特定序列，包括5'和3'剪接位点以及分支点，以确保精确剪接。虽然可变剪接对于正常细胞功能至关重要，但其失调越来越多地与癌症发病机制相关。异常剪接可导致致癌异构体的产生，促进肿瘤发生、转移和对治疗的抗性。此外，这种异常可导致肿瘤抑制活性的丧失，从而促进癌症发展。重要的是，异常的可变剪接事件可产生新抗原，这些新抗原通过主要组织相容性复合体（MHC）分子呈现在肿瘤细胞表面，提示癌症免疫治疗的新靶点。此外，剪接转换寡核苷酸（SSOs）已显示出作为治疗剂的前景，因为它们可调节剪接模式以恢复正常基因功能或诱导肿瘤抑制异构体。本综述探讨了癌症中可变剪接失调的机制、其在肿瘤进展中的作用及其作为治疗靶点的潜力。我们还讨论了高通量测序和计算方法等创新技术，这些技术正在彻底改变癌症中可变剪接的研究。最后，我们阐述了针对可变剪接进行个性化癌症治疗所面临的挑战和未来前景，强调了其在精准医学中的潜力。
