The progression of colorectal cancer (CRC) is strongly influenced by hypoxia, which is a key characteristic of the tumor microenvironment. Although circular RNAs (circRNAs) are implicated in cancer biology, their roles in hypoxia-driven CRC remain poorly defined. Here, we identified a novel hypoxia-induced circRNA, circ0005397 , that was significantly up-regulated in CRC and correlated with advanced stage, metastasis, and poor survival. Under hypoxic conditions, HIF1α directly initiated transcription by binding its promoter, whereas EIF4A3 facilitated circularization and nuclear export. Mechanistically, circ0005397 acts as a competitive endogenous RNA to absorb miR-330-5p, leading to MAPK1-mediated epithelial-to-mesenchymal transition activation, thereby enhancing tumor metastasis. Importantly, siRNA-mediated targeting of circ0005397 reversed epithelial-to-mesenchymal transition and overcame metastasis in patient-derived xenograft models. Our findings establish the HIF1α/EIF4A3/ circ0005397 /miR-330-5p/MAPK1 axis as a central hypoxia-responsive pathway in CRC and highlight circ0005397 as a promising diagnostic biomarker and therapeutic target for CRC.
Li et al. (Fri,) studied this question.