Deciphering the role of circular RNAs in cancer progression under hypoxic conditions

Hypoxia, characterized by reduced oxygen levels, plays a pivotal role in cancer progression, profoundly influencing tumor behavior and therapeutic responses. A hallmark of solid tumors, hypoxia drives significant metabolic adaptations in cancer cells, primarily mediated by hypoxia-inducible factor-1α (HIF-1α), a key transcription factor activated in low-oxygen conditions. This hypoxic environment promotes epithelial-mesenchymal transition (EMT), enhancing cancer cell migration, metastasis, and the development of cancer stem cell-like properties, which contribute to therapy resistance. Moreover, hypoxia modulates the expression of circular RNAs (circRNAs), leading to their accumulation in the tumor microenvironment. These hypoxia-responsive circRNAs regulate gene expression and cellular processes critical for cancer progression, making them promising candidates for diagnostic and prognostic biomarkers in various cancers. This review delves into the intricate interplay between hypoxic circRNAs, microRNAs, and RNA-binding proteins, emphasizing their role as molecular sponges that modulate gene expression and signaling pathways involved in cell proliferation, apoptosis, and metastasis. It also explores the relationship between circRNAs and the tumor microenvironment, particularly how hypoxia influences their expression and functional dynamics. Additionally, the review highlights the potential of circRNAs as diagnostic and prognostic tools, as well as their therapeutic applications in innovative cancer treatments. By consolidating current knowledge, this review underscores the critical role of circRNAs in cancer biology and paves the way for future research aimed at harnessing their unique properties for clinical advancements. Specifically, this review examines the biogenesis, expression patterns, and mechanistic actions of hypoxic circRNAs, focusing on their ability to act as molecular sponges for microRNAs and their interactions with RNA-binding proteins. These interactions impact key signaling pathways related to tumor growth, metastasis, and drug resistance, offering new insights into the complex regulatory networks governed by circRNAs under hypoxic stress.