Fig. 3: The roles and underlying mechanisms of hypoxia-responsive circRNAs played in tumor hypoxic environment.

I: Biogenesis of cirRNAs under hypoxia. The hypoxia-responsive circRNAs may be induced in either HIFs-dependent or independent manners. II: Some hypoxia-responsive circRNAs can reversely regulate the expression of HIFs by serving as miRNA sponge. III: Some hypoxia-responsive circRNAs act as miRNAs sponge to regulate the expression of hypoxia-responsive genes (not HIFs). IV: A few hypoxia responsive circRNAs can decoy nuclear proteins by inhibiting their nucleus translocation. For instance, circZNF292 binds SOX9 protein in cytoplasm to inhibit its nuclear translocation. V: Some hypoxia-responsive circRNAs can be encapsulated in exosomes. For example, hsa-circ-0048117 is significantly enriched in and secreted by exosomes of hypoxia pre-challenged esophageal squamous cell carcinoma (ESCC) cells and contributes to M2 macrophage polarization. (See the text for details).