Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
Bioinformatics Center, Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan.
Cell Rep. 2018 Apr 3;23(1):297-312.e12. doi: 10.1016/j.celrep.2018.03.064.
Long noncoding RNAs (lncRNAs) are commonly dysregulated in tumors, but only a handful are known to play pathophysiological roles in cancer. We inferred lncRNAs that dysregulate cancer pathways, oncogenes, and tumor suppressors (cancer genes) by modeling their effects on the activity of transcription factors, RNA-binding proteins, and microRNAs in 5,185 TCGA tumors and 1,019 ENCODE assays. Our predictions included hundreds of candidate onco- and tumor-suppressor lncRNAs (cancer lncRNAs) whose somatic alterations account for the dysregulation of dozens of cancer genes and pathways in each of 14 tumor contexts. To demonstrate proof of concept, we showed that perturbations targeting OIP5-AS1 (an inferred tumor suppressor) and TUG1 and WT1-AS (inferred onco-lncRNAs) dysregulated cancer genes and altered proliferation of breast and gynecologic cancer cells. Our analysis indicates that, although most lncRNAs are dysregulated in a tumor-specific manner, some, including OIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergistically dysregulate cancer pathways in multiple tumor contexts.
长链非编码 RNA（lncRNAs）在肿瘤中通常失调，但已知只有少数在癌症中发挥病理生理作用。我们通过模拟它们对 5185 个 TCGA 肿瘤和 1019 个 ENCODE 测定中转录因子、RNA 结合蛋白和 microRNAs 活性的影响，推断出失调癌症途径、癌基因和肿瘤抑制基因（癌症基因）的 lncRNAs。我们的预测包括数百个候选癌基因和肿瘤抑制基因 lncRNAs（癌症 lncRNAs），其体细胞改变导致 14 种肿瘤环境中数十种癌症基因和途径的失调。为了证明概念验证，我们表明针对 OIP5-AS1（推断的肿瘤抑制基因）和 TUG1 和 WT1-AS（推断的癌基因 lncRNAs）的扰动会失调癌症基因并改变乳腺癌和妇科癌症细胞的增殖。我们的分析表明，尽管大多数 lncRNAs 以肿瘤特异性方式失调，但包括 OIP5-AS1、TUG1、NEAT1、MEG3 和 TSIX 在内的一些 lncRNAs 在多种肿瘤环境中协同失调癌症途径。
