FAT10直接稳定HIF1α调控其表达促进肿瘤血管新生的机制研究

我们发现FAT10在肿瘤中高表达并稳定底物从而促进肿瘤侵袭转移（Cancer Research, 2014，2016）。肿瘤发生侵袭转移主要原因是血管新生，而HIF1α在调控血管新生中起重要作用，其E3酶VHL促进HIF1α经泛素降解从而抑制血管新生。但FAT10与HIF1α间关系尚不清楚。前期在VHL+/+肿瘤细胞和动物模型中发现：干扰FAT10导致HIF1α表达下降从而抑制肿瘤血管新生；免疫共沉淀结果发现FAT10与HIF1α结合；抑制蛋白酶体降解可阻断FAT10对HIF1α的调控。而在VHL-/-肿瘤细胞也发现上述现象，提示FAT10抑制HIF1α泛素化降解不依赖VHL。综上，我们推测FAT10通过直接稳定HIF1α的表达抑制其泛素化降解从而促进肿瘤血管新生。为验证假说，本课题拟采用裸鼠成瘤、体外泛素化等实验从动物、细胞和分子等水平探讨其具体机制，为抑制肿瘤血管新生提供新的理论依据。

Our study had demonstrated that FAT10 was highly expressed in tumor and stabilized the substrate to promote tumor invasion and metastasis (Cancer Research, 2014 and 2016). The main cause of tumor invasion and metastasis was angiogenesis. HIF1α plays an important role in angiogenesis, and its E3 enzyme VHL promotes ubiquitination degradation of HIF1α to inhibit tumor angiogenesis. However, the relationship between FAT10 and HIF1α remains unclear. Our previous study found that, in VHL+/+ tumor cells and animal models, knockdown of FAT10 decreased HIF1α expression to inhibit tumor angiogenesis. The result of Co-IP had showed the interaction between FAT10 and HIF1α. Inhibition of proteasome degradation could block FAT10-mediated regulation of HIF1α expression. However, the above phenomenon was also found in VHL-/- tumor cells, suggested that FAT10 inhibited the degradation of HIF1α via E3 enzyme VHL-independent pathway. In summary, we speculated that FAT10 directly stabilizes HIF1α expression and represses its ubiquitination degradation to promote tumor angiogenesis. In order to verify the hypothesis, in this study, its specific mechanisms will be explored at the animal, cellular and molecular levels by using nude mouse tumorigenicity assay and in vitro ubiquitination assay. This study will provide a new theoretical basis for inhibiting tumor angiogenesis.