Wang Bi-Dar, Lee Norman H
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland Eastern Shore, Princess Anne, MD 21853, USA.
Department of Pharmacology and Physiology, School of Medicine and Health Sciences, George Washington University, GW Cancer Center, Washington, DC 20037, USA.
Cancers (Basel). 2018 Nov 20;10(11):458. doi: 10.3390/cancers10110458.
More than 95% of the 20,000 to 25,000 transcribed human genes undergo alternative RNA splicing, which increases the diversity of the proteome. Isoforms derived from the same gene can have distinct and, in some cases, opposing functions. Accumulating evidence suggests that aberrant RNA splicing is a common and driving event in cancer development and progression. Moreover, aberrant splicing events conferring drug/therapy resistance in cancer is far more common than previously envisioned. In this review, aberrant splicing events in cancer-associated genes, namely , , , , , , , , , and , will be discussed. Also highlighted are the functional consequences of aberrant splice variants (, , , , , and ) in promoting resistance to cancer targeted therapy or immunotherapy. To overcome drug resistance, we discuss opportunities for developing novel strategies to specifically target the aberrant splice variants or splicing machinery that generates the splice variants. Therapeutic approaches include the development of splice variant-specific siRNAs, splice switching antisense oligonucleotides, and small molecule inhibitors targeting splicing factors, splicing factor kinases or the aberrant oncogenic protein isoforms.
在2万到2.5万个转录的人类基因中，超过95%会发生可变RNA剪接，这增加了蛋白质组的多样性。源自同一基因的异构体可能具有不同的功能，在某些情况下甚至具有相反的功能。越来越多的证据表明，异常RNA剪接是癌症发生和发展中的常见驱动事件。此外，赋予癌症药物/治疗抗性的异常剪接事件比以前预想的更为常见。在本综述中，将讨论癌症相关基因中的异常剪接事件，即 、 、 、 、 、 、 、 、 和 。还强调了异常剪接变体（ 、 、 、 、 、 和 ）在促进对癌症靶向治疗或免疫治疗的抗性方面的功能后果。为了克服耐药性，我们讨论了开发新策略以特异性靶向异常剪接变体或产生剪接变体的剪接机制的机会。治疗方法包括开发剪接变体特异性小干扰RNA、剪接转换反义寡核苷酸，以及靶向剪接因子、剪接因子激酶或异常致癌蛋白异构体的小分子抑制剂。
