Goel Anshita, Ward Douglas G, Gordon Naheema S, Abbotts Ben, Zeegers Maurice P, Cheng K K, James Nicholas D, Bryan Richard T, Arnold Roland
Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
NUTRIM School for Nutrition and Translational Research in Metabolism & CAPHRI Care and Public Health Research Institute, Maastricht University, Maastricht, Netherlands.
Front Oncol. 2020 May 22;10:812. doi: 10.3389/fonc.2020.00812. eCollection 2020.
Circularized transcript isoforms due to back-splicing are increasingly being reported in different tissues types and pathological states including cancer. Since these circular RNAs (circRNAs) are more stable than linear messenger RNA their identification and profiling in tumor tissue could aid in stratifying patients and may serve as biomarkers. In this study, we have investigated the relationship between circRNA expression and tumor grade in a cohort of 58, mostly non-muscle-invasive bladder cancer patients. From 4571 circRNAs detected, we identified 157 that were significantly differentially expressed between tumor grades relative to the linear transcript. We demonstrated that such grade-related differences can be identified in an independent cohort, and that a large fraction of circRNAs can be, in principle, detected in urine. The differentially expressed circRNAs cluster into subgroups according to their co-expression, subgroups which are enriched for DNA repair, cell cycle and intracellular signaling genes. Since one proposed function of circRNAs is to interfere with gene-regulation by acting as microRNA "sponges," candidates which were differentially expressed between tumor grades were investigated for potential miRNA target sites. By investigating the circRNAs from bladder cancer related pathways we demonstrated that the expression of these pathways, the circRNAs, and their parental genes are often decoupled and do not correlate, yet that some circRNAs do not follow this tendency. The present study provides the next step for the comprehensive evaluation of this novel class of RNAs in the context of non-muscle-invasive bladder cancer. Intriguingly, despite their possible function as microRNA sponges, they potentially affect host mRNA levels at the transcriptional stage, as compared to post-transcriptional control by miRNAs. Our analysis indicates differences of their activity between bladder cancer tumor stages, and their relative expression levels may provide an additional layer of information for patient stratification.
由于反向剪接产生的环状转录本异构体在包括癌症在内的不同组织类型和病理状态中越来越多地被报道。由于这些环状RNA（circRNA）比线性信使RNA更稳定，因此在肿瘤组织中对它们进行鉴定和分析有助于对患者进行分层，并可能作为生物标志物。在本研究中，我们调查了58例（大多为非肌层浸润性膀胱癌患者）队列中circRNA表达与肿瘤分级之间的关系。从检测到的4571种circRNA中，我们鉴定出157种相对于线性转录本在肿瘤分级之间存在显著差异表达的circRNA。我们证明了这种分级相关差异可以在一个独立队列中被识别，并且原则上大部分circRNA可以在尿液中被检测到。差异表达的circRNA根据其共表达情况聚类成亚组，这些亚组富含DNA修复、细胞周期和细胞内信号传导基因。由于circRNA的一个推测功能是通过充当微小RNA“海绵”来干扰基因调控，因此我们研究了在肿瘤分级之间差异表达的候选circRNA的潜在微小RNA靶位点。通过研究膀胱癌相关途径中的circRNA，我们证明了这些途径、circRNA及其亲本基因的表达通常是解耦的且不相关，但有些circRNA并不遵循这种趋势。本研究为在非肌层浸润性膀胱癌背景下对这类新型RNA进行全面评估提供了下一步。有趣的是，尽管它们可能具有作为微小RNA海绵的功能，但与微小RNA的转录后调控相比，它们可能在转录阶段影响宿主mRNA水平。我们的分析表明它们在膀胱癌肿瘤分期之间的活性存在差异，并且它们的相对表达水平可能为患者分层提供额外的信息层。
