Comprehensive characterization of alternative splicing in renal cell carcinoma
Comprehensive characterization of alternative splicing in renal cell carcinoma
复制标题
肾细胞癌选择性剪接的综合表征
DOI：
10.1093/bib/bbab084
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发表时间：
2021-04-05
影响因子：
9.5
通讯作者：
Xu, Hua
中科院分区：
文献类型：
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作者：
Zhang, Yangjun;Wu, Xiaoliang;Xu, Hua
不规则剪接与肾细胞癌（RCC）和许多其他癌症的肿瘤形成和进展相关。利用TCGA SpliceSeq数据库中的剪接数据，对RCC进行亚型分类，并系统分析剪接特征及其与临床病程、遗传变异、剪接因素、途径激活和免疫异质性的相关性。在这项研究中，选择性剪接被发现用于分类RCC亚型。剪接效率低下，内含子保留和盒式外显子上调与晚期肾癌患者的病情和不利的总生存率相关。剪接位点强度、鸟嘌呤和胞嘧啶含量以及外显子长度等剪接特征可能是破坏RCC剪接平衡的重要因素。除了顺式作用和反式作用调节外，选择性剪接还在种族和组织类型中存在差异，并且还受到突变条件，途径设置和对环境变化的反应的影响。肿瘤组织中严重的不规则剪接不仅表明细胞内的稳态异常，而且通过不同的剪接效应（包括异构体转换和表达调控）改变了肿瘤相关通路的活性。此外，不规则剪接和剪接相关抗原参与免疫重编程和免疫抑制肿瘤微环境的形成。总之，我们已经描述了RCC剪接亚型的几个临床和分子特征，这可能对患者管理和靶向治疗很重要。
Irregular splicing was associated with tumor formation and progression in renal cell carcinoma (RCC) and many other cancers. By using splicing data in the TCGA SpliceSeq database, RCC subtype classification was performed and splicing features and their correlations with clinical course, genetic variants, splicing factors, pathways activation and immune heterogeneity were systemically analyzed. In this research, alternative splicing was found useful for classifying RCC subtypes. Splicing inefficiency with upregulated intron retention and cassette exon was associated with advanced conditions and unfavorable overall survival of patients with RCC. Splicing characteristics like splice site strength, guanine and cytosine content and exon length may be important factors disrupting splicing balance in RCC. Other than cis-acting and trans-acting regulation, alternative splicing also differed in races and tissue types and is also affected by mutation conditions, pathway settings and the response to environmental changes. Severe irregular splicing in tumor not only indicated terrible intra-cellular homeostasis, but also changed the activity of cancer-associated pathways by different splicing effects including isoforms switching and expression regulation. Moreover, irregular splicing and splicing-associated antigens were involved in immune reprograming and formation of immunosuppressive tumor microenvironment. Overall, we have described several clinical and molecular features in RCC splicing subtypes, which may be important for patient management and targeting treatment.