The role of circular RNAs in driving cancer advancement in low-oxygen conditions

Oxygen shortage, or hypoxia, is a unifying feature of solid tumors that broadly characterizes cancer biology and therapeutic outcome. In expanding tumors, cells adapt to low oxygen tensions by undergoing extensive metabolic reorganization, which is mainly orchestrated by hypoxia-inducible factor-1α (HIF-1α). The adaptive response initiates epithelial-mesenchymal transition (EMT), promotes metastatic dissemination, and facilitates the formation of cancer stem-like states that drive therapy resistance. Apart from such cellular reorganization, hypoxia also affects circular RNA (circRNA) biogenesis and function, a unique category of non-coding RNAs. CircRNAs are deposited into the tumor microenvironment to function as gene-expression regulators and signaling cascade modulators that are critical for survival, invasion, and drug resistance. Their unique hypoxia-associated expression patterns render them the first choice for diagnosis and prognosis. In this work, we examine the intricate relationship between circRNAs and hypoxia as well as associated molecular mechanisms. We also emphasize their role as ceRNAs, about microRNA binding and RNA-binding proteins, and their oncogenic role. Finally, we underscore the potential of targeting hypoxia-responsive circRNAs as novel therapeutic strategies for cancer.