Hypoxia is a classic feature of the tumor microenvironment, and has been established as a key epigenetic factor modulating the outcome of radiotherapy. Circular RNAs (circRNAs) are novel RNA molecules with covalently closed circular structures and are highly expressed in eukaryotic transcriptomes. Although previous analysis have shown that circRNA ZNF292 (cZNF292) was hypoxia-responsive and exhibited a proangiogenic function in vitro, the molecular mechanism of cZNF292's biological function is still unclear and deserves further exploration. In this study, we investigated the effect of cZNF292 on the vasculogenic mimicry (VM) and radiosensitivity of hypoxic hepatoma SMMC7721 cells and its mechanism. Our data indicated that cZNF292 could be induced by hypoxia in a time-dependent manner in hepatoma cells independent of hypoxia inducible factor (HIF)-1α. Knockdown of cZNF292 increased SRY (sex determining region Y)-box 9 (SOX9) nuclear translocation, subsequently reduced Wnt/β-catenin pathway activity, leading to suppression of hypoxic hepatoma cell proliferation, VM, and radioresistance in vitro and in vivo. Our results delineated a novel mechanism of cZNF292 in enhancing hypoxic tumor cell radiosensitivity, which might provide valuable targets for radiation therapy for hepatoma.
Keywords: Hypoxia; Radioresistance; SOX9; circRNA ZNF292; β-catenin.
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