Figure 5.

Two examples of a positive feedback regulation of circRNAs expression, as seen in hepatocellular cancer. circ-LRIG3 and circ-SOD2 promote tumor progression through the activation of JAK/STAT signaling. More specifically, circ-LRIG3 acts as a protein scaffold, assisting the methylation of STAT3 by EZH2 and its subsequent phosphorylation, while circ-SOD2 acts as a competitive endogenous RNA and upregulates DNMT3A, which in turn suppresses the inhibitory role of SOCS3 in STAT3 activation. In both cases, activated STAT3 binds to the respective gene promoters and enhances their transcription, thus forming a positive feedback loop. Green arrows denote induction of expression, whereas the red “reverse tau” symbol (⊥) indicates attenuation of expression. Vertical green and red arrows indicate increased or decreased expression levels, respectively. Black arrows signify increased transcription rates, while dark blue arrows indicate the sequence of events in the feedback loops.