El Marabti Ettaib, Younis Ihab
Biological Sciences Program, Carnegie Mellon University in Qatar, Doha, Qatar.
Front Mol Biosci. 2018 Sep 7;5:80. doi: 10.3389/fmolb.2018.00080. eCollection 2018.
Alternative splicing allows for the expression of multiple RNA and protein isoforms from one gene, making it a major contributor to transcriptome and proteome diversification in eukaryotes. Advances in next generation sequencing technologies and genome-wide analyses have recently underscored the fact that the vast majority of multi-exon genes under normal physiology engage in alternative splicing in tissue-specific and developmental-specific manner. On the other hand, cancer cells exhibit remarkable transcriptome alterations partly by adopting cancer-specific splicing isoforms. These isoforms and their encoded proteins are not insignificant byproducts of the abnormal physiology of cancer cells, but either drivers of cancer progression or small but significant contributors to specific cancer hallmarks. Thus, it is paramount that the pathways that regulate alternative splicing in cancer, including the splicing factors that bind to pre-mRNAs and modulate spliceosome recruitment. In this review, we present a few distinct cases of alternative splicing in cancer, with an emphasis on their regulation as well as their contribution to cancer cell phenotype. Several categories of splicing aberrations are highlighted, including alterations in cancer-related genes that directly affect their pre-mRNA splicing, mutations in genes encoding splicing factors or core spliceosomal subunits, and the seemingly mutation-free disruptions in the balance of the expression of RNA-binding proteins, including components of both the major (U2-dependent) and minor (U12-dependent) spliceosomes. Given that the latter two classes cause global alterations in splicing that affect a wide range of genes, it remains a challenge to identify the ones that contribute to cancer progression. These challenges necessitate a systematic approach to decipher these aberrations and their impact on cancer. Ultimately, a sufficient understanding of splicing deregulation in cancer is predicted to pave the way for novel and innovative RNA-based therapies.
可变剪接使得一个基因能够表达多种RNA和蛋白质异构体，这使其成为真核生物转录组和蛋白质组多样化的主要促成因素。新一代测序技术和全基因组分析的进展最近突出了这样一个事实，即在正常生理条件下，绝大多数多外显子基因以组织特异性和发育特异性的方式进行可变剪接。另一方面，癌细胞部分地通过采用癌症特异性剪接异构体表现出显著的转录组改变。这些异构体及其编码的蛋白质并非癌细胞异常生理的无关紧要的副产物，而是癌症进展的驱动因素，或者是对特定癌症特征有小但显著贡献的因素。因此，至关重要的是了解癌症中调节可变剪接的途径，包括与前体mRNA结合并调节剪接体募集的剪接因子。在这篇综述中，我们介绍了癌症中一些不同的可变剪接案例，重点是它们的调节以及它们对癌细胞表型的贡献。突出了几类剪接异常，包括直接影响其前体mRNA剪接的癌症相关基因的改变、编码剪接因子或核心剪接体亚基的基因突变，以及RNA结合蛋白表达平衡中看似无突变的破坏，包括主要（U2依赖性）和次要（U12依赖性）剪接体的成分。鉴于后两类会导致影响广泛基因的剪接全局改变，识别那些促成癌症进展的改变仍然是一项挑战。这些挑战需要一种系统的方法来破译这些异常及其对癌症的影响。最终，对癌症中剪接失调的充分理解预计将为基于RNA的新型创新疗法铺平道路。
