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

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.