H19, a Long Non-coding RNA, Mediates Transcription Factors and Target Genes through Interference of MicroRNAs in Pan-Cancer

Aimin Li; Saurav Mallik; Haidan Luo; Peilin Jia; Dung-Fang Lee; Zhongming Zhao

doi:10.1016/j.omtn.2020.05.028

H19, a Long Non-coding RNA, Mediates Transcription Factors and Target Genes through Interference of MicroRNAs in Pan-Cancer

Mol Ther Nucleic Acids. 2020 Sep 4:21:180-191. doi: 10.1016/j.omtn.2020.05.028. Epub 2020 May 27.

Authors

Aimin Li¹, Saurav Mallik², Haidan Luo³, Peilin Jia², Dung-Fang Lee⁴, Zhongming Zhao⁵

Affiliations

¹ 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.
² Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
³ Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
⁴ Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Center for Stem Cell and Regenerative Medicine, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA. Electronic address: dung-fang.lee@uth.tmc.edu.
⁵ Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA; Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN 37203, USA. Electronic address: zhongming.zhao@uth.tmc.edu.

Abstract

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.

Keywords: H19; breast cancer; co-regulation; lncRNA; lncRNA-TF-gene; miRNA; pan-cancer; regulation triplet.