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TP promotes malignant progression in hepatocellular carcinoma through pentose Warburg effect

By Qiang Zhang, Yuan Qin, Jianmin Zhao, Yuanhao Tang, Xuejiao Hu, Weilong Zhong, Mimi Li, Shumin Zong, Meng Li, Honglian Tao, Zhen Zhang, Shuang Chen, Huijuan Liu, Lan Yang, Honggang Zhou, Yanrong Liu, Tao Sun, Cheng Yang

Posted 07 Aug 2018
bioRxiv DOI: 10.1101/386706

Tumor progression is dependent on metabolic reprogramming. Metastasis and vasculogenic mimicry (VM) are typical tumor progression. The relationship of metastasis, VM and metabolic reprogramming is not clear. In this study, we identified the novel role of Twist1, a VM regulator, in the transcriptional regulation of the expression of thymidine phosphorylase (TP). We demonstrated that TP promoted extracellular thymidine metabolization into ATP and amino acids through 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. TP inhibitor tipiracil reduced promotion effect of TP enzyme activity on HCC VM formation and metastasis. Our findings demonstrate that TP, transcriptionally activated by Twist1, promotes HCC VM formation and metastasis through pentose Warburg effect, contributing to tumor progression.

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