Global identification and characterization of tRNA-derived RNA fragment landscapes across human cancers.
Global identification and characterization of tRNA-derived RNA fragment landscapes across human cancers.
复制标题
人类癌症中 tRNA 衍生的 RNA 片段景观的全球鉴定和表征
作者：
Sun X;Yang J;Yu M;Yao D;Zhou L;Li X;Qiu Q;Lin W;Lu B;Chen E;Wang P;Chen W;Tao S;Xu H;Williams A;Liu Y;Pan X;Cowley AW Jr;Lu W;Liang M;Liu P;Lu Y
摘要转移RNA衍生的RNA片段（transfer RNA-derived RNA fragments，tRFs）是一类在许多生物体中大量存在的小分子非编码RNA，但其在肿瘤中的作用尚未得到充分研究。在这里，我们报告了来自癌症基因组图谱的15种癌症类型的8118份标本中tRFs的功能基因组景观。这些tRFs具有广泛表达、序列高度保守、细胞质定位、特异的tRNA切割模式和组织中保守切割等特点。一项跨肿瘤分析显示，来自不同来源组织的tRF表达亚型之间存在显著的共性，其特征在于具有相似大小的一组tRF的上调和癌症相关信号的激活。其中最大的一个超簇由13种癌症类型中上调的22个nt 3′-tRFs组成，所有这些肿瘤都具有Ras/MAPK、RTK和TSC/mTOR信号转导的激活。基于tRF的亚组提供了临床相关分层，并通过纳入临床变量显著改善了结局预测。此外，我们发现了11个癌症驱动因子tRF，使用有效的方法准确探索跨肿瘤和平台趋势。作为概念验证，我们对非microRNA驱动tRF 5′-IleAAT-8-1-L20进行了全面的功能测定，并在体外和体内验证了其在肺癌中的致癌作用。我们的研究也为识别诊断和预后生物标志物，开发癌症治疗和研究癌症发病机制提供了宝贵的tRF资源。
Abstract Transfer RNA-derived RNA fragments (tRFs) are a class of small non-coding RNAs that are abundant in many organisms, but their role in cancer has not been fully explored. Here, we report a functional genomic landscape of tRFs in 8118 specimens across 15 cancer types from The Cancer Genome Atlas. These tRFs exhibited characteristics of widespread expression, high sequence conservation, cytoplasmic localization, specific patterns of tRNA cleavage and conserved cleavage in tissues. A cross-tumor analysis revealed significant commonality among tRF expression subtypes from distinct tissues of origins, characterized by upregulation of a group of tRFs with similar size and activation of cancer-associated signaling. One of the largest superclusters was composed of 22 nt 3′-tRFs upregulated in 13 cancer types, all of which share the activation of Ras/MAPK, RTK and TSC/mTOR signaling. tRF-based subgrouping provided clinically relevant stratifications and significantly improved outcome prediction by incorporating clinical variables. Additionally, we discovered 11 cancer driver tRFs using an effective approach for accurately exploring cross-tumor and platform trends. As a proof of concept, we performed comprehensive functional assays on a non-microRNA driver tRF, 5′-IleAAT-8-1-L20, and validated its oncogenic roles in lung cancer in vitro and in vivo. Our study also provides a valuable tRF resource for identifying diagnostic and prognostic biomarkers, developing cancer therapy and studying cancer pathogenesis.