Zhang Guimin, Liu Binrui, Yang Yun, Xie Shuo, Chen Lingcheng, Luo Hui, Zhong Jian, Wei Yinhao, Guo Fengzhu, Gan Jia, Zhu Fan, Xu Lin, Li Qiqi, Shen Yuge, Zhang Huajin, Liu Yan, Li Rong, Deng Hongxin, Yang Hanshuo
Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
Department of Medical Oncology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, China.
iScience. 2023 Jul 13;26(8):107370. doi: 10.1016/j.isci.2023.107370. eCollection 2023 Aug 18.
Mitochondria play important roles in angiogenesis. However, the mechanisms remain elusive. In this study, we found that mitochondrial ubiquinol-cytochrome c reductase complex assembly factor 3 (UQCC3) is a key regulator of angiogenesis. TALEN-mediated knockout of in mice caused embryonic lethality at 9.5-10.5 days postcoitum, and vessel density was dramatically reduced. Similarly, knockout of in zebrafish induced lethality post-fertilization and impaired vascular development. Knockout of resulted in slower tumor growth and angiogenesis. Mechanistically, UQCC3 was upregulated under hypoxia, promoted reactive oxygen species (ROS) generation, enhanced HIF-1α stability and increased VEGF expression. Finally, higher expression of was associated with poor prognosis in multiple types tumors, implying a role for UQCC3 in tumor progression. In conclusion, our findings highlight the important contribution of UQCC3 to angiogenesis under both physiological and pathological conditions, indicating the potential of UQCC3 as a therapeutic target for cancer.
线粒体在血管生成中发挥着重要作用。然而，其机制仍不清楚。在本研究中，我们发现线粒体泛醇 - 细胞色素c还原酶复合物组装因子3（UQCC3）是血管生成的关键调节因子。TALEN介导的小鼠体内UQCC3基因敲除导致妊娠后9.5 - 10.5天胚胎致死，血管密度显著降低。同样，斑马鱼体内UQCC3基因敲除导致受精后致死，并损害血管发育。UQCC3基因敲除导致肿瘤生长和血管生成减缓。机制上，UQCC3在缺氧条件下上调，促进活性氧（ROS）生成，增强HIF - 1α稳定性并增加VEGF表达。最后，UQCC3在多种类型肿瘤中的高表达与不良预后相关，这意味着UQCC3在肿瘤进展中发挥作用。总之，我们的研究结果突出了UQCC3在生理和病理条件下对血管生成的重要贡献，表明UQCC3作为癌症治疗靶点的潜力。
