Li Aimin, Mallik Saurav, Luo Haidan, Jia Peilin, Lee Dung-Fang, Zhao Zhongming
Shaanxi Key Laboratory for Network Computing and Security Technology, School of Computer Science and Engineering, Xi'an University of Technology, Xi'an, Shaanxi 710048, China; Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Mol Ther Nucleic Acids. 2020 Sep 4;21:180-191. doi: 10.1016/j.omtn.2020.05.028. Epub 2020 May 27.
Long non-coding RNAs (lncRNAs) have recently been found to be important in gene regulation. lncRNA H19 has been reported to play an oncogenic role in many human cancers. Its specific regulatory role is still elusive. In this study, we developed a novel analytic approach by integrating the synergistic regulation among lncRNAs (e.g., H19), transcription factors (TFs), target genes, and microRNAs (miRNAs) and then applied it to the pan-cancer expression datasets from The Cancer Genome Atlas (TCGA). Using linear regression models, we identified 88 H19-TF-gene co-regulatory triplets, in which 93% of the TF-gene pairs were related to cancer, indicating that our approach was effective to identify disease-related lncRNA-TF-gene co-regulation mechanisms. lncRNAs can function as miRNA sponges. Our further experiments found that H19 might regulate SP1-TGFBR2 through let-7b and miR-200b, ETS1-TGFBR2 through miR-29a and miR-200b, and STAT3-KLF11 through miR-17 in breast cancer cell lines. Our work suggests that miRNA-mediated lncRNA-TF-gene co-regulation is complicated yet important in cancer.
长链非编码RNA（lncRNAs）最近被发现对基因调控具有重要作用。据报道，lncRNA H19在许多人类癌症中发挥致癌作用。其具体的调控作用仍不清楚。在本研究中，我们通过整合lncRNAs（如H19）、转录因子（TFs）、靶基因和微小RNA（miRNAs）之间的协同调控，开发了一种新的分析方法，然后将其应用于来自癌症基因组图谱（TCGA）的泛癌表达数据集。使用线性回归模型，我们鉴定出88个H19-TF-基因共调控三联体，其中93%的TF-基因对与癌症相关，这表明我们的方法有效地识别了与疾病相关的lncRNA-TF-基因共调控机制。lncRNAs可以作为miRNA海绵发挥作用。我们进一步的实验发现，在乳腺癌细胞系中，H19可能通过let-7b和miR-200b调控SP1-TGFBR2，通过miR-29a和miR-200b调控ETS1-TGFBR2，通过miR-17调控STAT3-KLF11。我们的工作表明，miRNA介导的lncRNA-TF-基因共调控在癌症中虽然复杂但很重要。
