State Key Laboratory of Medicine Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China.
Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, China.
Cell Death Dis. 2019 Jan 17;10(2):43. doi: 10.1038/s41419-018-1282-6.
Tumor progression is dependent on metabolic reprogramming. Metastasis and vasculogenic mimicry (VM) are typical characteristics of tumor progression. The relationship among metastasis, VM, and metabolic reprogramming remains unclear. In this study, we identified the novel role of Twist1, a VM regulator, in the transcriptional regulation of thymidine phosphorylase (TP) expression. TP promoted the extracellular metabolism of thymidine into ATP and amino acids through the pentose Warburg effect by coupling the pentose phosphate pathway and glycolysis. Moreover, Twist1 relied on TP-induced metabolic reprogramming to promote hepatocellular carcinoma (HCC) metastasis and VM formation mediated by VE-Cad, VEGFR1, and VEGFR2 in vitro and in vivo. The TP inhibitor tipiracil reduced the effect of TP on promoting HCC VM formation and metastasis. Hence, TP, when transcriptionally activated by Twist1, promotes HCC VM formation and metastasis through the pentose Warburg effect and contributes to tumor progression.
肿瘤的进展依赖于代谢重编程。转移和血管生成拟态（VM）是肿瘤进展的典型特征。转移、VM 和代谢重编程之间的关系尚不清楚。在这项研究中，我们确定了 Twist1（一种 VM 调节因子）在胸苷磷酸化酶（TP）表达的转录调控中的新作用。TP 通过戊糖磷酸途径和糖酵解的偶联，将胸苷的细胞外代谢转化为 ATP 和氨基酸，从而促进戊糖沃伯格效应。此外，Twist1 依赖于 TP 诱导的代谢重编程，在体外和体内促进肝癌（HCC）转移和由 VE-Cad、VEGFR1 和 VEGFR2 介导的 VM 形成。TP 抑制剂替皮拉西可降低 TP 促进 HCC VM 形成和转移的作用。因此，当 Twist1 转录激活 TP 时，TP 通过戊糖沃伯格效应促进 HCC VM 形成和转移，并促进肿瘤进展。
