Transcription Factors and Methylation Drive Prognostic miRNA Dysregulation in Hepatocellular Carcinoma

Many dysregulated microRNAs (miRNAs) have been suggested to serve as oncogenes or tumor suppressors to act as diagnostic and prognostic factors for HCC patients. However, the dysregulated mechanisms of miRNAs in HCC remain largely unknown. Herein, we firstly identify 114 disordered mature miRNAs in HCC, 93 of them are caused by dysregulated transcription factors, and 10 of them are driven by the DNA methylation of their promoter regions. Secondly, we find that seven up-regulated miRNAs (miR-9-5p, miR-452-5p, miR-452-3p, miR-1180-3p, miR-4746-5p, miR-3677-3 and miR-4661-5p) can promote tumorigenesis via inhibiting multiple tumor suppressor genes participated in metabolism, which may act as oncogenes, and seven down-regulated miRNAs (miR-99-5p, miR-5589-5p, miR-5589-3p, miR-139-5p, miR-139-3p, miR-101-3p and miR-125b-5p) can suppress abnormal cell proliferation via suppressing a number of oncogenes involved in cancer-related pathways, which may serve as tumor suppressors. Thirdly, our findings reveal a mechanism that transcription factor and miRNA interplay can form various regulatory loops to synergistically control the occurrence and development of HCC. Finally, our results demonstrate that this key transcription factor FOXO1 can activate a certain number of tumor suppressor miRNAs to improve the survival of HCC patients, suggesting FOXO1 as an effective therapeutic target for HCC patients. Overall, our study not only reveals the dysregulated mechanisms of miRNAs in HCC, but provides several novel prognostic biomarkers and potential therapeutic targets for HCC patients.