Key Enzymes in Pyrimidine Synthesis, CAD and CPS1, Predict Prognosis in Hepatocellular Carcinoma
Patients with hepatocellular carcinoma (HCC) have a highly variable clinical course. Therefore, there is an urgent need to identify new prognostic markers to determine prognosis and select specific therapies. Recently, it has been demonstrated that dysregulation of the urea cycle (UC) is a common ph...
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MDPI AG
2021-02-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/4/744 |
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| author | Dirk Andreas Ridder Mario Schindeldecker Arndt Weinmann Kristina Berndt Lana Urbansky Hagen Roland Witzel Stefan Heinrich Wilfried Roth Beate Katharina Straub |
| author_facet | Dirk Andreas Ridder Mario Schindeldecker Arndt Weinmann Kristina Berndt Lana Urbansky Hagen Roland Witzel Stefan Heinrich Wilfried Roth Beate Katharina Straub |
| author_sort | Dirk Andreas Ridder |
| collection | DOAJ |
| description | Patients with hepatocellular carcinoma (HCC) have a highly variable clinical course. Therefore, there is an urgent need to identify new prognostic markers to determine prognosis and select specific therapies. Recently, it has been demonstrated that dysregulation of the urea cycle (UC) is a common phenomenon in multiple types of cancer. Upon UC dysregulation, nitrogen is diverted toward the multifunctional enzyme carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase (CAD), and increases pyrimidine synthesis. In this study, we investigated the role of CAD and carbamoyl-phosphate synthetase 1 (CPS1), a rate-limiting enzyme of the UC highly expressed in hepatocytes, in HCC. We created a tissue microarray to analyze expression of both enzymes by immunohistochemistry in a large and well-characterized overall cohort of 871 HCCs of 561 patients that underwent surgery. CAD was induced in recurrent HCCs, and high expression predicted shorter overall survival. CPS1 was downregulated in HCC and further reduced in recurrent tumors and distant metastases. Additionally, low CPS1 was associated with short overall survival. A combined score of both enzymes was an independent prognostic marker in a multivariate Cox regression model (HR = 1.37, 95% confidence interval 1.06–1.75, <i>p</i> = 0.014). Inhibition of pyrimidine synthesis may represent a novel therapeutic strategy for HCC. |
| first_indexed | 2024-03-09T04:44:42Z |
| format | Article |
| id | doaj.art-2db7741bccbc4d5c9ff9d599f0d283ae |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T04:44:42Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-2db7741bccbc4d5c9ff9d599f0d283ae2023-12-03T13:17:08ZengMDPI AGCancers2072-66942021-02-0113474410.3390/cancers13040744Key Enzymes in Pyrimidine Synthesis, CAD and CPS1, Predict Prognosis in Hepatocellular CarcinomaDirk Andreas Ridder0Mario Schindeldecker1Arndt Weinmann2Kristina Berndt3Lana Urbansky4Hagen Roland Witzel5Stefan Heinrich6Wilfried Roth7Beate Katharina Straub8Institute of Pathology, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, GermanyInstitute of Pathology, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, GermanyDepartment of Internal Medicine, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, GermanyInstitute of Pathology, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, GermanyInstitute of Pathology, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, GermanyInstitute of Pathology, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, GermanyDepartment of General, Visceral and Transplant Surgery, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, GermanyInstitute of Pathology, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, GermanyInstitute of Pathology, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, GermanyPatients with hepatocellular carcinoma (HCC) have a highly variable clinical course. Therefore, there is an urgent need to identify new prognostic markers to determine prognosis and select specific therapies. Recently, it has been demonstrated that dysregulation of the urea cycle (UC) is a common phenomenon in multiple types of cancer. Upon UC dysregulation, nitrogen is diverted toward the multifunctional enzyme carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase (CAD), and increases pyrimidine synthesis. In this study, we investigated the role of CAD and carbamoyl-phosphate synthetase 1 (CPS1), a rate-limiting enzyme of the UC highly expressed in hepatocytes, in HCC. We created a tissue microarray to analyze expression of both enzymes by immunohistochemistry in a large and well-characterized overall cohort of 871 HCCs of 561 patients that underwent surgery. CAD was induced in recurrent HCCs, and high expression predicted shorter overall survival. CPS1 was downregulated in HCC and further reduced in recurrent tumors and distant metastases. Additionally, low CPS1 was associated with short overall survival. A combined score of both enzymes was an independent prognostic marker in a multivariate Cox regression model (HR = 1.37, 95% confidence interval 1.06–1.75, <i>p</i> = 0.014). Inhibition of pyrimidine synthesis may represent a novel therapeutic strategy for HCC.https://www.mdpi.com/2072-6694/13/4/744hepatocellular carcinomaHCCprognosisbiomarkerpyrimidinecps1 |
| spellingShingle | Dirk Andreas Ridder Mario Schindeldecker Arndt Weinmann Kristina Berndt Lana Urbansky Hagen Roland Witzel Stefan Heinrich Wilfried Roth Beate Katharina Straub Key Enzymes in Pyrimidine Synthesis, CAD and CPS1, Predict Prognosis in Hepatocellular Carcinoma Cancers hepatocellular carcinoma HCC prognosis biomarker pyrimidine cps1 |
| title | Key Enzymes in Pyrimidine Synthesis, CAD and CPS1, Predict Prognosis in Hepatocellular Carcinoma |
| title_full | Key Enzymes in Pyrimidine Synthesis, CAD and CPS1, Predict Prognosis in Hepatocellular Carcinoma |
| title_fullStr | Key Enzymes in Pyrimidine Synthesis, CAD and CPS1, Predict Prognosis in Hepatocellular Carcinoma |
| title_full_unstemmed | Key Enzymes in Pyrimidine Synthesis, CAD and CPS1, Predict Prognosis in Hepatocellular Carcinoma |
| title_short | Key Enzymes in Pyrimidine Synthesis, CAD and CPS1, Predict Prognosis in Hepatocellular Carcinoma |
| title_sort | key enzymes in pyrimidine synthesis cad and cps1 predict prognosis in hepatocellular carcinoma |
| topic | hepatocellular carcinoma HCC prognosis biomarker pyrimidine cps1 |
| url | https://www.mdpi.com/2072-6694/13/4/744 |
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