癸基泛醌上调BAI1抑制肿瘤血管形成的作用及其机制研究

Angiogenesis is involved in the development, progression and metastasis of various human cancers. By high-throughput screening of a FDA approved drug library, we identified that decylubiquinone (DUb), an analogue of coenzyme Q10, had a potent anti-angiogenic effect. We firstly revealed that DUb inhibited blood vessel formation and development in chick embryo chorioallantoic membrane (CAM) and yolk sac membrane (YSM) assay; meanwhile, it also restricted the tumor growth in xenograft mouse model. Using spontaneous tumor mouse model, we demonstrated that DUb significantly hampered tumor angiogenesis, growth and metastasis. We further showed DUb also suppressed endothelial cell migration and the formation of tubular structures, and disclosed that DUb inhibited angiogenesis by up-regulating the expression of brain-specific angiogenesis inhibitor 1 (BAI1). These data suggest that DUb is able to act as a potential anti-tumor drug through its ability to inhibit angiogenesis.

肿瘤血管形成对肿瘤生长及转移至关重要。癸基泛醌(Decylubiquinone,DUb)是辅酶Q10的类似物，对肿瘤血管形成的作用尚未见报道。我们通过高通量筛药发现DUb能抑制鸡胚血管形成，并能显著地抑制血管内皮细胞的迁移和成管；重要的是还能显著抑制胰岛β细胞瘤、自发乳腺癌和黑色素瘤的血管形成和生长转移；基因芯片筛查发现DUb能显著上调血管发生抑制基因BAI1（脑特异性血管生成抑制因子1）的表达。以上结果提示DUb可能通过上调BAI1表达抑制肿瘤血管形成，从而抑制肿瘤生长和转移；而其具体分子机制尚未明确。基于上述结果及文献报道，我们推测DUb通过激活wt p53-BAI1-Vstat120-CD36信号通路抑制肿瘤血管形成。本项目将以基因工程小鼠、鸡胚血管等研究体系，阐明DUb抑制肿瘤血管形成的作用及分子机制，从而为DUb成为一种新的抗肿瘤血管形成的药物提供理论依据。