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

// Hsi-Wen Yeh 1, 2 , Szu-Shuo Lee 2, 3 , Chieh-Yu Chang 2, 4 , Chun-Mei Hu 5 and Yuh-Shan Jou 1, 2, 3, 4 1 Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan 2 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan 3 Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan 4 Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan 5 Genomic Research Center, Academia Sinica, Taipei, Taiwan Correspondence to: Yuh-Shan Jou, email: jou@ibms.sinica.edu.tw Keywords: hepatocellular carcinoma, poor differentiation, pyrimidine metabolism, rate-limiting enzymes, stemness Received: May 04, 2017 Accepted: July 29, 2017 Published: September 08, 2017 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 survival in multiple cohorts. Together, we identified aberrant pyrimidine pathway in poorly-differentiated HCC promotes cancer stemness served as potential theranostic target for battling HCC tumor progression.