文章：

RNA剪接失调和癌症的标志

RNA splicing dysregulation and the hallmarks of cancer

原文发布日期：2023-01-10

DOI: 10.1038/s41568-022-00541-7

类型: Review Article

开放获取: 否

英文摘要：

Dysregulated RNA splicing is a molecular feature that characterizes almost all tumour types. Cancer-associated splicing alterations arise from both recurrent mutations and altered expression of trans-acting factors governing splicing catalysis and regulation. Cancer-associated splicing dysregulation can promote tumorigenesis via diverse mechanisms, contributing to increased cell proliferation, decreased apoptosis, enhanced migration and metastatic potential, resistance to chemotherapy and evasion of immune surveillance. Recent studies have identified specific cancer-associated isoforms that play critical roles in cancer cell transformation and growth and demonstrated the therapeutic benefits of correcting or otherwise antagonizing such cancer-associated mRNA isoforms. Clinical-grade small molecules that modulate or inhibit RNA splicing have similarly been developed as promising anticancer therapeutics. Here, we review splicing alterations characteristic of cancer cell transcriptomes, dysregulated splicing’s contributions to tumour initiation and progression, and existing and emerging approaches for targeting splicing for cancer therapy. Finally, we discuss the outstanding questions and challenges that must be addressed to translate these findings into the clinic.

摘要翻译： 

RNA剪接失调是几乎所有肿瘤类型共有的分子特征。癌症相关剪接改变既源于反复出现的突变，也源于调控剪接催化和调节的反式作用因子表达改变。癌症相关剪接失调可通过多种机制促进肿瘤发生，包括增强细胞增殖、减少细胞凋亡、提高迁移和转移能力、产生化疗耐药性和逃避免疫监视。近期研究发现，特定癌症相关亚型在癌细胞转化和生长中起关键作用，并证实了纠正或拮抗这些癌症相关mRNA亚型可带来治疗获益。目前已完成临床级小分子药物的开发，这些能调节或抑制RNA剪接的药物已成为颇具前景的抗癌疗法。本文综述了癌细胞转录组的特征性剪接改变、剪接失调在肿瘤发生发展中的作用机制，以及当前与新兴的癌症剪接靶向治疗策略。最后，我们探讨了将研究成果转化为临床应用尚需解决的关键问题与挑战。

原文链接：

RNA splicing dysregulation and the hallmarks of cancer