Pyrimidine metabolic rate limiting enzymes in poorly-differentiated hepatocellular carcinoma are signature genes of cancer stemness and associated with poor prognosis

Oncotarget
Hsi-Wen YehYuh-Shan Jou

Abstract

Cellular metabolism of cancer cell is generally recognized to provide energy for facilitating tumor growth, but little is known about the aberrant metabolism in tumor progression and its prognostic value. Here, we applied integrated genomic approach to uncover the aberrant expression of metabolic enzymes in poorly-differentiated human hepatocellular carcinoma (HCC) for revealing targets against HCC malignancy. A total of 135 upregulated (22 are rate-limiting enzymes (RLEs)) and 362 down-regulated (77 are RLEs) metabolic genes were identified and associated with poor patient survival in large-cohorts of HCC patients in TCGA-LIHC and two other independent transcriptomic studies. Ten out of 22 upregulated RLEs in poorly-differentiated HCC are critical enzymes in pyrimidine metabolism pathways in association with stemness features by gene enrichment analysis and upregulated in ALDH1(+) stem-like HCC subpopulations. By focusing on three RLEs including TK1, TYMS and DTYMK of dTTP biosynthesis pathway, expression of 3 RLEs in well-differentiated HCC cells increased ALDH1(+) and spheroid stemness population but reversed by knockdown in poorly-differentiated HCC cells. Up-regulated 3 RLEs in HCC were associated with poor patient surviva...Continue Reading

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Citations

Jun 13, 2019·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Suet-Yan KwanWen Xue
Oct 18, 2019·Scientific Reports·Kenta TsunekuniHideshi Ishii
Nov 2, 2019·Nature Reviews. Gastroenterology & Hepatology·Letizia SatrianoJesper B Andersen
Mar 23, 2021·Gastroenterology Report·Daniel G TenenJustin L Tan

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Datasets Mentioned

BETA
GSE50579
GSE36411

Methods Mentioned

BETA
RNA-seq
NMR
reversed transcription PCR

Software Mentioned

RSEM
SPSS
GSEA

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