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

ABSTRACT: 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.

SUBMITTER: Zhang Q

PROVIDER: S-EPMC6426839 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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

Zhang Qiang Q Qin Yuan Y Zhao Jianmin J Tang Yuanhao Y Hu Xuejiao X Zhong Weilong W Li Mimi M Zong Shumin S Li Meng M Tao Honglian H Zhang Zhen Z Chen Shuang S Liu Huijuan H Yang Lan L Zhou Honggang H Liu Yanrong Y Sun Tao T Yang Cheng C

Cell death & disease 20190117 2

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 ...[more]

PMID: 30674871

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Project description:Background: Hepatocellular carcinoma (HCC) presents a common malignant tumor worldwide. Although kinectin 1 (KTN1) is the most frequently identified antigen in HCC tissues, the detailed roles of KTN1 in HCC remain unknown. This study seeks to clarify the expression status and clinical value of KTN1 in HCC and to explore the complicated biological functions of KTN1 and its underlying mechanisms. Methods: In-house reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression of KTN1 in HCC tissues. External gene microarrays and RNA-sequencing datasets were downloaded to confirm the expression patterns of KTN1. The prognostic ability of KTN1 in HCC was assessed by a Kaplan-Meier curve and a hazard ratio forest plot. The CRISPR/Cas9 gene-editing system was used to knock out KTN1 in Huh7 cells, which was verified by PCR-Sanger sequencing and western blotting. Assays of cell migration, invasion, viability, cell cycle, and apoptosis were conducted to explore the biological functions. RNA sequencing was performed to quantitatively analyze the functional deregulation in KTN1-knockout cells compared to Huh7-wild-type cells. Upregulated genes that co-expressed with KTN1 were identified from HCC tissues and were functionally annotated. Results: KTN1 expression was increased in HCC tissues (standardized mean difference [SMD] = 0.20 [0.04, 0.37]). High KTN1 expression was significantly correlated with poorer prognosis of HCC patients, and KTN1 may be an independent risk factor for HCC (pooled HRs = 1.31 [1.05, 1.64]). After KTN1-knockout, the viability, migration, and invasion ability of HCC cells were inhibited. The proportion of HCC cells in the G0-G1 phases increased after KTN1 knockout, which also elevated the apoptosis rates in HCC cells. Several cascades, including innate immune response, chemical carcinogenesis, and positive regulation of transcription by RNA polymerase II, were dramatically changed after KTN1 knockout. KTN1 primarily participated in the cell cycle, DNA replication, and microRNAs in cancer pathways in HCC tissues. Conclusion: Upregulation of KTN1 served as a promising prognosticator in HCC patients. KTN1 promotes the occurrence and deterioration of HCC by mediating cell survival, migration, invasion, cell cycle activation, and apoptotic inhibition. KTN1 may be a therapeutic target in HCC patients.

Dataset Information

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

Publications

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

Similar Datasets

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