大肠癌中的可变剪接事件及其临床意义:靶向治疗机会
Alternative Splicing Events and Their Clinical Significance in Colorectal Cancer: Targeted Therapeutic Opportunities.
发表日期:2023 Aug 07
作者:
Mosebo Armstrong Manabile, Rodney Hull, Richard Khanyile, Thulo Molefi, Botle Precious Damane, Nigel Patrick Mongan, David Owen Bates, Zodwa Dlamini
来源:
Cancers
摘要:
结直肠癌(CRC)是全球癌症死亡的主要原因之一,在低中等收入国家(LMICs)尤其严重。有几个因素会导致CRC的发展和进展。发现替代剪接(AS)是CRC发展和进展的分子机制之一。随着基因组/转录组测序和大量患者数据库的出现,异常AS在癌症发展和进展中的广泛作用已经变得清楚。AS影响癌症的启动、增殖、侵袭和迁移。这些剪接改变通过产生正常功能或具有不同甚至相反功能的变异蛋白质来活化癌基因或失活肿瘤抑制基因。因此,鉴定和表征CRC特异性替代剪接事件和变异体可能有助于设计新的治疗性剪接破坏剂药物。CRC特异性剪接事件可以用作诊断和预后的生物标志物。本综述将讨论替代剪接事件及其在CRC发展中的作用。本论文还回顾了最近关于可用作预后、诊断和靶向治疗指标的替代剪接事件的研究。特别感兴趣的是针对蛋白质精氨酸甲基转移酶(PMRT)的亚型进行靶向治疗和诊断工具的开发。还将讨论将这些发现转化为临床实践的潜在挑战和限制。
Colorectal cancer (CRC) ranks as one of the top causes of cancer mortality worldwide and its incidence is on the rise, particularly in low-middle-income countries (LMICs). There are several factors that contribute to the development and progression of CRC. Alternative splicing (AS) was found to be one of the molecular mechanisms underlying the development and progression of CRC. With the advent of genome/transcriptome sequencing and large patient databases, the broad role of aberrant AS in cancer development and progression has become clear. AS affects cancer initiation, proliferation, invasion, and migration. These splicing changes activate oncogenes or deactivate tumor suppressor genes by producing altered amounts of normally functional or new proteins with different, even opposing, functions. Thus, identifying and characterizing CRC-specific alternative splicing events and variants might help in designing new therapeutic splicing disrupter drugs. CRC-specific splicing events can be used as diagnostic and prognostic biomarkers. In this review, alternatively spliced events and their role in CRC development will be discussed. The paper also reviews recent research on alternatively spliced events that might be exploited as prognostic, diagnostic, and targeted therapeutic indicators. Of particular interest is the targeting of protein arginine methyltransferase (PMRT) isoforms for the development of new treatments and diagnostic tools. The potential challenges and limitations in translating these discoveries into clinical practice will also be addressed.