Positive Feedback Regulation of Circular RNA Hsa_circ_0000566 and HIF-1α promotes Osteosarcoma Progression and Glycolysis Metabolism.
Positive Feedback Regulation of Circular RNA Hsa_circ_0000566 and HIF-1α promotes Osteosarcoma Progression and Glycolysis Metabolism.
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DOI：
10.14336/ad.2022.0826
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发表时间：
2023-04-01
影响因子：
7.4
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中科院分区：
文献类型：
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缺氧是癌症进展不可缺少的因素，与Warburg效应密切相关。环状 RNA (CircRNA) 在分子恶性肿瘤治疗中引起了相当大的关注，因为它们是潜在的重要调节剂。然而，circRNA 和缺氧在骨肉瘤 (OS) 进展中的作用尚未阐明。这项研究揭示了缺氧敏感的 circRNA Hsa_circ_0000566，它在缺氧应激下的 OS 进展和能量代谢中发挥着至关重要的作用。 Hsa_circ_0000566 受缺氧诱导因子 1α (HIF-1α) 调节，并直接与其以及 Von Hippel-Lindau (VHL) E3 泛素连接酶蛋白结合。因此，VHL 和 HIF-1α 之间的结合受到阻碍。此外，Hsa_circ_0000566 通过与 HIF-1α 结合（同时与 VHL 竞争）并提供针对 HIF-1α 的保护以防止 VHL 介导的泛素降解，从而有助于 OS 进展。这些发现证明了 HIF-1α 和 Hsa_circ_0000566 形成的正反馈环路的存在以及它们在 OS 糖酵解中发挥的关键作用。总而言之，这些数据表明 Hsa_circ_0000566 在 Warburg 效应中的重要性，并表明 Hsa_circ_0000566 可能是对抗 OS 进展的潜在治疗靶点。
Hypoxia is an indispensable factor for cancer progression and is closely associated with the Warburg effect. Circular RNAs (CircRNA) have garnered considerable attention in molecular malignancy therapy as they are potentially important modulators. However, the roles of circRNAs and hypoxia in osteosarcoma (OS) progression have not yet been elucidated. This study reveals the hypoxia-sensitive circRNA, Hsa_circ_0000566, that plays a crucial role in OS progression and energy metabolism under hypoxic stress. Hsa_circ_0000566 is regulated by hypoxia-inducible factor-1α (HIF-1α) and directly binds to it as well as to the Von Hippel-Lindau (VHL) E3 ubiquitin ligase protein. Consequentially, binding between VHL and HIF-1α is impeded. Furthermore, Hsa_circ_0000566 contributes to OS progression by binding to HIF-1α (while competing with VHL) and by confers protection against HIF-1α against VHL-mediated ubiquitin degradation. These findings demonstrate the existence of a positive feedback loop formed by HIF-1α and Hsa_circ_0000566 and the key role they play in OS glycolysis. Taken together, these data indicate the significance of Hsa_circ_0000566 in the Warburg effect and suggest that Hsa_circ_0000566 could be a potential therapeutic target to combat OS progression.