Thymidine phosphorylase promotes malignant progression in hepatocellular carcinoma through pentose Warburg effect.

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.