Zhou Haitao, Wu Yanjin, Meng Jiahui, Zhao Xiaotong, Hou Yujia, Wang Qin, Liu Yang
State Key Laboratory of Advanced Medical Materials and Devices, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Tianjin Institutes of Health Science, Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, China.
Int J Mol Sci. 2025 May 9;26(10):4513. doi: 10.3390/ijms26104513.
C1QBP (Complement Component 1 Q Subcomponent-Binding Protein) plays a critical role in maintaining cellular metabolism, but its function in radiation-induced damage remains unclear. In this study, we generated C1QBP-deficient Huh-7 hepatocellular carcinoma (HCC) cells using CRISPR/Cas9 technology and observed that C1QBP deficiency significantly enhanced radiation-induced damage, as indicated by reduced cell proliferation, impaired colony formation, and increased γ-H2AX foci, a marker of DNA double-strand breaks. Additionally, C1QBP deficiency resulted in elevated phosphorylation of key DNA damage response (DDR) molecules, ATM and CHK2, and caused pronounced S phase cell cycle arrest. Mechanistic investigations revealed that C1QBP modulates NF-κB nuclear activity via the AMPK signaling pathway. The loss of C1QBP reduced NF-κB nuclear translocation, further exacerbating radiation-induced damage. Reintroducing C1QBP alleviated DNA damage, enhanced cell proliferation, and improved survival following radiation exposure. These findings highlight the critical role of C1QBP in modulating HCC cells radiosensitivity and underscore its potential as a therapeutic target to enhance radiotherapy outcomes.
补体成分1 Q亚成分结合蛋白（C1QBP）在维持细胞代谢中起关键作用，但其在辐射诱导损伤中的功能仍不清楚。在本研究中，我们使用CRISPR/Cas9技术生成了C1QBP缺陷的Huh-7肝癌（HCC）细胞，并观察到C1QBP缺陷显著增强了辐射诱导的损伤，表现为细胞增殖减少、集落形成受损以及γ-H2AX灶增加，γ-H2AX是DNA双链断裂的标志物。此外，C1QBP缺陷导致关键的DNA损伤反应（DDR）分子ATM和CHK2的磷酸化升高，并导致明显的S期细胞周期阻滞。机制研究表明，C1QBP通过AMPK信号通路调节NF-κB的核活性。C1QBP的缺失减少了NF-κB的核转位，进一步加剧了辐射诱导的损伤。重新引入C1QBP可减轻DNA损伤，增强细胞增殖，并改善辐射暴露后的存活率。这些发现突出了C1QBP在调节肝癌细胞放射敏感性中的关键作用，并强调了其作为增强放疗效果的治疗靶点的潜力。
