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.
Highlights
Hepatocellular carcinoma (HCC), the major malignancy of liver, is the sixth most common cancer in the world and the second leading cause of cancer deaths for the last decade with around 0.8 million each of new cases and deaths annually [1]
To determine the involvement of metabolic genes during tumor progression of hepatocellular carcinoma (HCC) especially focusing on tumor differentiation, we downloaded RNA transcriptomic datasets performed by generation sequencing (RNAseq) in The Cancer Genome Atlas (TCGA) project (TCGA-LIHC) containing 50 normal liver tissues and 357 HCC samples including 227 well-differentiated HCC (Grade I and II of histological grading) and 130 poorlydifferentiated HCC (Grade III and IV) and examined the expression status of 1,706 reported metabolic genes [23]
To determine the critical enzymes participated in these metabolic pathways, we further examined the driving rate-limiting enzymes (RLEs) [26] including 22 upregulated rate limiting enzymes (RLEs) and 77 downregulated RLEs participated in these altered metabolic pathways (Table 1)
Summary
Hepatocellular carcinoma (HCC), the major malignancy of liver, is the sixth most common cancer in the world and the second leading cause of cancer deaths for the last decade with around 0.8 million each of new cases and deaths annually [1]. Cancer cell aggressiveness is tightly associated with features of epithelial to mesenchymal transition (EMT), stemness, poor differentiation and high mobility of cancer cells leading to outcomes of drug resistance, recurrence and metastasis resulted in poor survival of cancer patients [21, 22]. To reveal how metabolic reprogramming contributes to aggressiveness and serves as theranostic target during tumor progression, we examined the altered expression of metabolic enzymes in association with histopathological feature of poor differentiation of HCC using the large number of HCC patients from TCGA cohorts. We identified a unique pyrimidine metabolic rate limiting enzymes (RLEs) gene signature that is altered in poorlydifferentiated HCC and correlated to the stemness of embryonic signatures and poor patient survival. With validations of experiments and HCC patients in multiple cohorts, we provided lines of evidence that TK1, TYMS and DTYMK the catalytic RLEs in pyrimidine biosynthesis play critical roles in cancer stemness and serve as potential therapeutic targets in poorlydifferentiated HCC
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