Wang Junqing, Wang Xiuquan, Bhat Akshay, Chen Yixin, Xu Keli, Mo Yin-Yuan, Yi Song Stephen, Zhou Yunyun
Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Mathematics and Computer Science, Tougaloo College, Jackson, MS, United States.
Front Genet. 2020 Jul 15;11:659. doi: 10.3389/fgene.2020.00659. eCollection 2020.
It is increasingly appreciated that long non-coding RNAs (lncRNAs) associated with alternative splicing (AS) could be involved in aggressive hepatocellular carcinoma. Although many recent studies show the alteration of RNA alternative splicing by deregulated lncRNAs in cancer, the extent to which and how lncRNAs impact alternative splicing at the genome scale remains largely elusive. We analyzed RNA-seq data obtained from 369 hepatocellular carcinomas (HCCs) and 160 normal liver tissues, quantified 198,619 isoform transcripts, and identified a total of 1,375 significant AS events in liver cancer. In order to predict novel AS-associated lncRNAs, we performed an integration of co-expression, protein-protein interaction (PPI) and epigenetic interaction networks that links lncRNA modulators (such as splicing factors, transcript factors, and miRNAs) along with their targeted AS genes in HCC. We developed a random walk-based multi-graphic (RWMG) model algorithm that prioritizes functional lncRNAs with their associated AS targets to computationally model the heterogeneous networks in HCC. RWMG shows a good performance evaluated by the ROC curve based on cross-validation and bootstrapping strategies. As a conclusion, our robust network-based framework has derived 31 AS-related lncRNAs that not only validates known cancer-associated cases MALAT1 and HOXA11-AS, but also reveals new players such as DNM1P35 and DLX6-AS1with potential functional implications. Survival analysis further provides insights into the clinical significance of identified lncRNAs.
越来越多的研究表明，与可变剪接（AS）相关的长链非编码RNA（lncRNA）可能参与侵袭性肝细胞癌的发生发展。尽管最近许多研究显示，癌症中lncRNA失调会改变RNA可变剪接，但lncRNA在基因组水平上对可变剪接的影响程度及作用方式仍不清楚。我们分析了来自369例肝细胞癌（HCC）和160例正常肝组织的RNA测序数据，对198,619个异构体转录本进行了定量分析，并在肝癌中总共鉴定出1,375个显著的可变剪接事件。为了预测新的与可变剪接相关的lncRNA，我们整合了共表达、蛋白质-蛋白质相互作用（PPI）和表观遗传相互作用网络，这些网络将lncRNA调节因子（如剪接因子、转录因子和微小RNA）与其在肝癌中的靶向可变剪接基因联系起来。我们开发了一种基于随机游走的多图谱（RWMG）模型算法，该算法通过对功能性lncRNA及其相关的可变剪接靶点进行优先级排序，从而对肝癌中的异质网络进行计算建模。基于交叉验证和自抽样策略的ROC曲线评估结果表明，RWMG具有良好的性能。总之，我们基于网络的强大框架已经推导得出31个与可变剪接相关的lncRNA，这些lncRNA不仅验证了已知的与癌症相关的病例MALAT1和HOXA11-AS，还揭示了新的参与者，如具有潜在功能意义的DNM1P35和DLX6-AS1。生存分析进一步深入了解了所鉴定lncRNA的临床意义。
