circRNA_104075 stimulates YAP-dependent tumorigenesis through the regulation of HNF4a and may serve as a diagnostic marker in hepatocellular carcinoma

Cell Death Dis. 2018 Oct 25;9(11):1091. doi: 10.1038/s41419-018-1132-6.

Abstract

Some types of circular RNA (circRNA) are aberrantly expressed in human diseases including hepatocellular carcinoma (HCC). However, its regulation mechanism and diagnostic roles are largely unknown. Here, we identified that circRNA_104075 (circ_104075) was highly expressed in HCC tissues, cell lines and serum. Mechanistically, HNF4a bound to the -1409 to -1401 region of the circ_104075 promoter to stimulate the expression of circ_104075. Moreover, circ_104075 acted as a ceRNA to upregulate YAP expression by absorbing miR-582-3p. Interestingly, an N6-methyladenosine (m6A) motif was identified in the 353-357 region of YAP 3'UTR, and this m6A modification was essential for the interaction between miR-582-3p and YAP 3'UTR. Further, the diagnostic performance of circ_104075 was evaluated. The area under the receiver operating characteristic (AUC-ROC) for circ_104075 was 0.973 with a sensitivity of 96.0% and a specificity of 98.3%. Collectively, we determined that circ_104075 was highly expressed in HCC and elucidated its upstream and downstream regulatory mechanisms. circ_104075 additionally has the potential to serve as a new diagnostic biomarker in HCC. Targeting circ_104075 may provide new strategies in HCC diagnosis and therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Adenosine / analogs & derivatives
  • Adenosine / metabolism
  • Adult
  • Aged
  • Animals
  • Biomarkers, Tumor / metabolism
  • Carcinogenesis / metabolism*
  • Carcinoma, Hepatocellular / blood
  • Carcinoma, Hepatocellular / metabolism*
  • Cell Survival
  • Female
  • Hep G2 Cells
  • Hepatocyte Nuclear Factor 4 / genetics
  • Hepatocyte Nuclear Factor 4 / metabolism*
  • Humans
  • Liver Neoplasms / blood
  • Liver Neoplasms / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • MicroRNAs / metabolism
  • Middle Aged
  • Promoter Regions, Genetic
  • Protein Interaction Domains and Motifs
  • RNA, Circular / metabolism*
  • ROC Curve
  • Transcription Factors / metabolism*
  • YAP-Signaling Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • Biomarkers, Tumor
  • HNF4A protein, human
  • Hepatocyte Nuclear Factor 4
  • Hnf4a protein, mouse
  • MIRN582 microRNA, human
  • MicroRNAs
  • RNA, Circular
  • Transcription Factors
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • N-methyladenosine
  • Adenosine