Chow Eugene Yui-Ching, Zhang Jizhou, Qin Hao, Chan Ting-Fung
School of Life Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Shatin, Hong Kong.
Front Genet. 2019 Nov 8;10:1081. doi: 10.3389/fgene.2019.01081. eCollection 2019.
Advances in sequencing technologies have greatly improved our understanding of long noncoding RNA (lncRNA). These transcripts with lengths of >200 nucleotides may play significant regulatory roles in various biological processes. Importantly, the dysregulation of better characterized lncRNAs has been associated with multiple types of cancers, including hepatocellular carcinoma (HCC). There are many studies on altered lncRNA expression levels, very few, however, have focused on their subcellular localizations, from which accumulating evidences have indicated their close relationships to lncRNA functions. A transcriptome-wide investigation of the subcellular distributions of lncRNAs might thus provide new insights into their roles and functions in cancers. In this study, we subjected eight patient-derived HCC cell lines to subcellular fractionation and independently sequenced RNAs from the nuclear and cytoplasmic compartments. With the integration of tumor and tumor-adjacent RNA-seq datasets of liver hepatocellular carcinoma (LIHC) from The Cancer Genome Atlas (TCGA), transcriptome assembly and differential expression analysis were conducted successively and identified 26 nuclear-enriched HCC-associated lncRNAs shared between the HCC samples and the TCGA datasets, including the reported cancer driver . The majority of nuclear-enriched HCC-associated lncRNAs were associated with the survival outcomes of HCC patients, exhibited characteristics similar to those of many experimentally supported HCC prognostic lncRNAs, and were co-expressed with protein-coding genes that have been linked to disease progression in various cancer types. We adopted a fractionation-then-sequencing approach on multiple patient-derived HCC samples and identified nuclear-enriched, HCC-associated lncRNAs that could serve as important targets for HCC diagnosis and therapeutic development. This approach could be widely applicable to other studies into the disease etiologies of lncRNA.
测序技术的进步极大地增进了我们对长链非编码RNA（lncRNA）的理解。这些长度大于200个核苷酸的转录本可能在各种生物学过程中发挥重要的调控作用。重要的是，特征更明确的lncRNAs的失调与多种类型的癌症相关，包括肝细胞癌（HCC）。关于lncRNA表达水平改变的研究有很多，然而，很少有研究关注它们的亚细胞定位，而越来越多的证据表明这与lncRNA功能密切相关。因此，对lncRNAs亚细胞分布进行全转录组研究可能会为其在癌症中的作用和功能提供新的见解。在本研究中，我们对8个患者来源的HCC细胞系进行了亚细胞分级分离，并分别对来自细胞核和细胞质部分的RNA进行了测序。通过整合来自癌症基因组图谱（TCGA）的肝细胞癌（LIHC）的肿瘤和肿瘤邻近RNA-seq数据集，相继进行了转录组组装和差异表达分析，鉴定出26个在HCC样本和TCGA数据集中共享的核富集HCC相关lncRNAs，包括已报道的癌症驱动因子。大多数核富集HCC相关lncRNAs与HCC患者的生存结果相关，表现出与许多实验支持的HCC预后lncRNAs相似的特征，并与在各种癌症类型中与疾病进展相关的蛋白质编码基因共表达。我们对多个患者来源的HCC样本采用了先分级分离后测序的方法，鉴定出了可作为HCC诊断和治疗开发重要靶点的核富集HCC相关lncRNAs。这种方法可广泛应用于lncRNA疾病病因的其他研究。
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