DataSheet1_CircFOXO3 upregulation mediates the radioresistance of glioblastoma by affecting cellular metabolome.DOCX

IntroductionRadioresistance remains a significant challenge in the treatment of glioblastoma multiforme (GBM), the most prevalent and lethal brain cancer in adults. Metabolic alterations are known to contribute to radioresistance by activating antioxidant responses and promoting DNA repair. However, the role of circular RNAs in this process, particularly circFOXO3, is not well understood.
MethodsIn this study, we investigated the expression of circFOXO3 in glioma cells exposed to radiation and in recurrent GBM tissues. We performed knockdown and overexpression experiments in vitro and in vivo to assess the effects of circFOXO3 on radiosensitivity. Metabolomic profiling was conducted to explore the metabolic changes associated with circFOXO3 overexpression following irradiation.
ResultsOur results showed significant upregulation of circFOXO3 in glioma cells upon radiation exposure and in recurrent GBM tissues. Knockdown of circFOXO3 increased radiosensitivity both in vitro and in vivo, whereas overexpression of circFOXO3 attenuated radiosensitivity. Metabolomic analysis revealed substantial alterations in lipid and organic compound profiles between circFOXO3-overexpressing and control groups. Additionally, circFOXO3 suppression increased proapoptotic protein levels (Caspase 7 and Bax) and decreased anti-apoptotic protein Bcl-2 levels following radiotherapy.
DiscussionThese findings demonstrate the pivotal role of circFOXO3 in promoting tumor radioresistance through metabolic modulation, suggesting that circFOXO3 could serve as a potential diagnostic and therapeutic target for GBM.

引言：放射抵抗仍是成人最常见且致死率最高的原发性脑恶性肿瘤——多形性胶质母细胞瘤（glioblastoma multiforme, GBM）治疗中的重大挑战。已知代谢改变可通过激活抗氧化应答、促进DNA修复介导肿瘤放射抵抗，但环状RNA（circular RNA, circRNA）在该过程中的作用，尤其是circFOXO3，尚未得到充分阐明。
方法：本研究检测了受辐射处理的胶质瘤细胞以及复发型GBM组织中circFOXO3的表达水平。我们分别在体外及体内开展了circFOXO3的敲低与过表达实验，以评估其对肿瘤放射敏感性的影响。此外，本研究通过代谢组学分析，探究了辐射后circFOXO3过表达所伴随的代谢改变。
结果：本研究结果显示，受辐射处理的胶质瘤细胞以及复发型GBM组织中，circFOXO3的表达水平显著上调。敲低circFOXO3可在体外及体内提升肿瘤的放射敏感性，而过表达circFOXO3则会削弱其放射敏感性。代谢组学分析结果显示，circFOXO3过表达组与对照组之间的脂质及有机化合物谱存在显著差异。此外，放疗后circFOXO3的抑制可提升促凋亡蛋白（半胱氨酸天冬氨酸蛋白酶7，Caspase 7；Bcl-2相关X蛋白，Bax）的表达水平，并降低抗凋亡蛋白B细胞淋巴瘤-2（B-cell lymphoma 2, Bcl-2）的表达水平。
讨论：本研究结果证实了circFOXO3通过代谢调控介导肿瘤放射抵抗的关键作用，提示circFOXO3可作为GBM潜在的诊断与治疗靶点。